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THE 



MEDICAL CLINICS 



OE NORTH AMERICA 




SYPHILIS AND OTHER 
VENEREAL DISEASES 

VOLUME 48 - NUMBER 3 
MAY, 1964 



IS:; 



VANDERBILT UNIVERSITY NUMBER 



THE 

MEDICAL CLINICS 

OF NORTH AMERICA 



SYPHILIS AND OTHER VENEREAL DISEASES 

A Symposium in Honor of 
Rudolph H. Kampmeier 



JOHN B. YOUMANS, M.D. 

Guest Editor 



Volume 48 — Number 3 
MAY, 1964 



W. B. SAUNDERS COMPANY - Philadelphia & London 



© 1964 by W. B. Saunders Company. Copyright under the International Copyright 
Union. All rights reserved. This publication is protected by copyright. No part of it 
may be duplicated or reproduced in any manner without written permission of the 
publisher. Made in the United States of America. Press of W. B. Saunders Company. 

The following information is published in accordance with the requirements of the United States 
Postal Code. 

The Medical Clinics of North America is published every other month by W. B. Saunders Company, 
West Washington Square, Philadelphia 5, Pennsylvania at Hampton Road, Cherry Hill, New Jersey. 
Subscription price is $18.00 per year. Second-class postage paid at Haddonfield, New Jersey. 

This issue is Volume 48, Number 3. 

The editor of this publication is Dwight J. Hotchkiss, W. B. Saunders Company, West Washington 
Square, Philadelphia 5, Pennsylvania 

Library of Congress catalog card number 17-28505 



Contributors to This Issue 



BOBBY C. BROWN, M.D., Assistant to the Chief, Venereal Disease Branch, Commu- 
nicable Disease Center, Bureau of State Services, Public Health Service, Depart- 
ment of Health, Education, and Welfare, Atlanta, Georgia. 

WILLIAM J. BROWN, M.D., Chief, Venereal Disease Branch, Communicable Dis- 
ease Center, U.S. PubHc Health Service, Atlanta, Georgia, 

E. GURNEY CLARK, M.D., Dr.P.H., Professor of Epidemiology, College of Physicians 
and Surgeons, New York, N.Y. 

KYRIL B. CONGER, M.D., Professor of Urology, Temple University School of Medi- 
cine, Philadelphia, Pennsylvania. 

ARTHUR C. CURTIS, M.D., Professor and Chairman, Department of Dermatology, 
University of Michigan Medical School, Ann Arbor, Michigan. 

NIELS DANBOLT, M.D., Professor of Dermatology and Syphilology, University of 
Oslo, Norway. 

WILLIAM F. DANEHOWER, M.D., Physician, Department of General Practice, 
Germantown Hospital, Philadelphia, Pennsylvania. 

WILLIAM L. FLEMING, M.D., Chaimian, Department of Preventive Medicine, 
School of Medicine, University of North Carolina, Chapel Hill, North Carolina. 

WILLIAM W. FRYE, Ph.D., M.D., Vice-President, Louisiana State University, and 
Dean of its School of Medicine, New Orleans, Louisiana; Chairman, Combined 
Dean's Committee, Veterans Administration Hospitals; U.S.P.H.S. Advisory 
Committee on Allergy and Infectious Diseases; Member, Armed Forces Epi- 
demic Board on Enteric Diseases, Washington, D.C. 

EUGENE J. GILLESPIE, M.D., Deputy Chief, Venereal Disease Branch, Communi- 
cable Disease Center, Bureau of State Services, Public Health Service, Depart- 
ment of Health, Education, and Welfare, Atlanta, Georgia. 

CHARLES L. HUDSON, M.D., Board of Trustees, American Medical Association; 
Associate Professor of Medicine, Cleveland Clinic Educational Foundation; 
Associate CHnical Professor of Medicine, Western Reserve University School 
of Medicine, Cleveland, Ohio. 

JOHN C. HUME, M.D., Dr.P.H., Professor of PubHc Health Administration, The 
Johns Hopkins University, Baltimore, Maryland, 

R. H. KAMPMEIER, M.D., Professor of Medicine, Emeritus, and Director of Con- 
tinuing Education, Vanderbilt University School of Medicine, Nashville, 
Tennessee. 



iv Contributors to This Issue 

M. BRITTAIN MOORE, JR., M.D., Director, Venereal Disease Research Laboratory, 
Venereal Disease Branch, Communicable Disease Center, U.S. Public Health 
Service, Atlanta, Georgia. 

SIDNEY OLANSKY, M.D., Professor of Medicine (Dermatology), Emory University 
School of Medicine, Emory University Clinic, Atlanta, Georgia. 

HARRY PARISER, M.D., D.Sc. (Med.), Director, Venereal Disease Control Program, 
Norfolk, Virginia. 

OSGOODE S. PHILPOTT, JR., M.D., Department of Dermatology, University of 
Michigan Medical School, Ann Arbor, Michigan. 

D. B. STEWART, M.D., Professor of Obstetrics and Gynaecology, University of the 
West Indies, Jamaica. 

ANNE SWEENEY, M.A., Medical Social Service Department, Vanderbilt University 
Hospital, Nashville, Tennessee. 

JAMES D. THAYER, Ph.D., Chief, Antibiotic Surveillance and Methodology Lab- 
oratory Research and Development, Venereal Disease Branch, Communicable 
Disease Center, U.S. Public Health Service, Atlanta, Georgia. 

EVAN W. THOMAS, M.D., Consultant to Chicago Board of Health, Chicago, Illinois. 

JOHN F. WILSON, M.D., M.S., Associate Professor of Dermatology and Syphilology, 
Jefferson Medical College; Visiting Lecturer in Dermatology and Syphilology, 
Graduate School, University of Pennsylvania; Chief Dermatologist, Presbyterian 
and Roxborough Memorial Hospitals; Attending Dermatologist, Misericordia 
Hospital, Philadelphia, Pennsylvania. 

JOHN B. YOUMANS, M.D., Emeritus Professor of Medicine, Vanderbilt University 
School of Medicine, Nashville, Tennessee; President, United Health Foundations, 
Inc., The New York Academy of Medicine, New York, N.Y. 



Table of Contents 

SYMPOSIUM ON SYPHILIS AND 
OTHER VENEREAL DISEASES 



Dedicatory Foreword 571 

John B. Youmans, M.D., Guest Editor 

Role of Public Health and Private Medicine in the 

Eradication of Syphilis 573 

William J. Brown, M.D. 

What the American Medical Association is Doing About 

Syphilis 583 

Charles L. Hudson, M.D. 



SPECIAL DISTRIBUTION OF THIS ISSUE 

At the request of the United States Public Health Service, the 
publishers have agreed to make available to Health Departments 
extra copies of this issue for presentation to selected physicians in 
the United States. The Public Health Service feels that the infor- 
mation contained in this symposium is of vital importance to 
national health and that its distribution should not be restricted 
solely to subscribers to the Medical Clinics. 



Syphilis Through the Ages 587 

William L. Fleming, M.D. 

The Oslo Study of the Natural Course of Untreated 
Syphilis: An Epidemiologic Investigation Based on a 

Re-study of the Boeck-Bruusgaard Material 613 

£. Gurney Clark, M.D., Dr.P.H.; Niels Danholt, M.D. 



VI Table of Contents 
Infectious Syphilis 625 

Harry Pariser, M.D. D.Sc. (Med.) 

The Importance of Contact Investigation in the Control 

OF Syphilis 637 

William W. Frye, Ph.D., M.D. 
Discussion by William J. Brown, M.D 649 

Late Benign Syphilis ( Gumma ) 653 

Sidney Olansky, M.D. 

The Late Manifestations of Syphilis: Skeletal, Visceral 

AND Cardiovascular 667 

R. H. Kampmeier, M.D. 

Some Aspects of Neurosyphilis 699 

Evan W. Thomas, M.D. 

Prenatal Syphilis 707 

Arthur C. Curtis, M.D.; Osgoode S. Philpott, Jr., M.D. 

Worldwide Problems in the Diagnosis of Syphilis and 

Other Treponematoses 721 

John C. Hume, M.D., Dr.P.H. 

New Laboratory Methods in the Diagnosis and Management 

OF Syphilis 731 

Eugene J. Gillespie, M.D.; Bobby C. Brown, M.D. 

A Glance in Both Directions— The Impact of Syphilis 

ON the Family 743 

Anne Sweeney, M.A. 

Penicillin Fallout and Infectious Syphilis 747 

William F. Danehower, M.D. 

Gonorrhea: Present Knowledge, Research and Control 

Efforts 755 

James D. Thayer, Ph.D.; M. Brittain Moore, Jr., M.D. 



Table of Contents vii 

Gonorrhea and Nonspecific Urethritis 767 

Kyril B. Conger, M.D. 

The Gynecological Lesions of Lymphogranuloma Venereum 

AND Granuloma Inguinale 773 

D. B. Stewart, M.D. 

The Nonvenereal Diseases of the Genitals: Their Differentiation 

from Venereal Lesions 787 

John F. Wihon, M.D. 

Appendix: A Summary of The Treatment of Syphilis, with Notes on 
Prognosis and Follow-up 811 

Cumulative Index 815 



RECENT SYMPOSIA 

July, 1963— from Philadelphia 
Diseases of the Kidney 

September, 196S— Nationwide 
Infections Today 

November, 1Q6S— Nationwide 
Neurologic Disturbances 

January, 1964— Chicago 

Diseases of the Digestive Tract 

March, 1964— N ationwide 

Efficacy of New Drugs 

FORTHCOMING SYMPOSIA 

July, 1964— from Mayo Clinic 

Diseases of the Respiratory Tract 
Matthew^ B. Divertie, M.D. 
W. Spencer Payne, M.D. 
Guest Editors 

September, 1964— N ationwide 

1. Obesity 

2. Recent Advances in Applied Nutrition 

Seymour Lionel Halpern, M.D., Guest Editor 

November, 1964 

1. Medical Aspects of Trauma 

Geisinger Medical Center, Danville, Pa. 

2. Commonly Referred Problems 

Hunterdon Medical Center, Flemington, N.J. 

January, 1965— Chicago 

Diseases of Muscles, Bones and Joints 

Edw^ard F. Rosenberg, M.D., Guest Editor 

March, 1965-Boston 

Adolescent Medicine 

J. Rosw^ell Gallagher, Guest Editor 




RUDOLPH H. KAMPMEIER, M.D. 

Born January 15, 1898, at Clarksville, Iowa. A.B. and M.D., State University of Iowa. 
Instructor, University of Michigan Medical School, 1925-1929. Assistant Professor and 
Clinical Professor of Medicine, Louisiana State University Medical Center and Attending 
Physician, Charity Hospital, New Orleans, 1932-1936. Assistant Professor, Associate 
Professor and Professor of Medicine, 1936-1963, and Director of Continuing Education, 
1963-, Vanderbilt University School of Medicine. In charge of Vanderbilt University 
Hospital Syphilis Clinic, 1936-1952 and Director of Postgraduate Courses in Syphilis 
for Public Health Officers and Nurses, 1937-1943. President, Tennessee Medical Associa- 
tion, 1964. President-Elect, Southern Medical Association, 1964. Fellow (1928-), Gover- 
nor for Tennessee (1954-1961) and Regent (1961-), American College of Physicians. 
Editor, Southern Medical Journal (1955-) and Tennessee Medical Journal (1950-). 
Author of Essentials in Syphilology (1943) and Physical Examination in Health and 
Disease (3rd Ed., 1964). Some eighty published medical papers. 



SYMPOSIUM ON SYPHILIS AND 
OTHER VENEREAL DISEASES 

Dedicatory Foreword 



In a period in medicine when highly sophisticated and complex 
procedures have supplemented and indeed supplanted much of the personal 
detection, identification and evaluation of the manifestations and mecha- 
nisms of disease, those due to pathogenic micro-organisms remain a group 
less affected than others. Among these, syphilis is the captain. In no other 
disease does the need for acute and accurate observation by the use of the 
five senses for the detection of physical signs and symptoms, for their 
interpretation and evaluation, for the information obtained from the 
patient and a limited variety of laboratory tests, all supported by inductive 
and deductive reasoning based on experience, play so great a part in 
diagnosis, in prognosis and in judgment as to treatment. 

It is eminently fitting, therefore, that this volume of collected papers 
dealing with syphilis and other venereal diseases, themselves in many 
instances both historically and at present complicating the diagnosis and 
management of the great pox, should be dedicated, as was the symposium 
on which it was based, to Dr. R. H. Kampmeier. An accomplished diag- 
nostitian, a consummate clinician, an inspiring teacher and a distinguished 
editorialist, as a syphilologist he deservedly ranks with the most distin- 
guished physicians in the field in modern times. Nor is this all. By its very 
nature, by its demoniac versatility and mimicry, syphilis demands for 
competence in its diagnosis and management a corresponding competence 
in the whole field of internal medicine. Indeed, it is to an eminent internist 
and teacher, a distinguished physician of physicians that this volume is a 
highly deserved, if inadequate, tribute. 

John B. Youmans, M.D. 
Guest Editor 
2 East 103rd Street 
New York 29, N. Y. 



571 



Role of Public Health and Private 
Medicine in the Eradication of Syphilis 

WILLIAM J. BROWN, M.D.* 



I don't believe that there is any one in this audience who does 
not respect both truth and logic. Therefore, because the subject which I 
am about to discuss is both of great importance and great urgency, I hope 
you will permit me to be both frank and analytical. And I hope you will 
accept what I have to say in the spirit in which I say it. 

It is not my intention to be critical, but rather to explore realistically 
the problems surrounding the epidemiology of syphilis, problems of great 
concern to both public health and private medicine. 

I don't know how many of you read the editorial entitled ''Why the 
Increasing Incidence of Syphilis?" in the March 30, 1963 issue of the 
Journal of the American Medical Association. Those of you who did may 
remember that it asked the following questions : 

''Why, in 1963, has there been a sudden reawakening of interest in a 
disease which had seemed more or less forgotten? What is the urgency 
which surrounds syphilis and its control?" Let's think about this for a few 
minutes. 

Once Syphilis Ravaged Nations 

Syphilis, I suppose, is as old as man himself; or almost as old anyway. 
It has been considered one of the great plagues of mankind. At least once 
in recorded history, it swept an entire continent in a relatively short time, 
killing literally millions of persons, and crippling millions more. In fact, 
smallpox, which today we consider not only frightening, but absolutely 
intolerable down to the last single case, was named in contrast to a then 
much more formidable disease; and that disease was, of course, the great 
pox — or, as we call it now, "syphilis." 



Read at, Syphilis: A Symposium, Vanderbilt University School of Medicine, Nashville, 

Tennessee, May 17-18, 1963. 
* Chief, Venereal Disease Branch, Communicable Disease Center, U. S. Public Health 

Service, Atlanta, Georgia 

573 



574 William J. Brown 

Actually, although the treponeme seems to have become somewhat 
less virulent after the eighteenth century, syphilis continued to do a 
fantastic amount of damage right down through a good part of the twen- 
tieth century. 

Then Came Penicillin, Quick Office Cures and De-emphasis 

Penicillin, of course, was introduced into syphilotherapy in the 40's 
with such dramatic results that it was considered by many to be the 
so-called ''breakthrough" that mankind had been working toward and 
hoping for for centuries; and all over the country, people who probably 
should have known better hailed the eradication of syphilis as a foregone 
conclusion. The statistics seemed to bear out this thesis, because infectious 
syphilis dropped from a 1947 high of more than 100,000 reported cases to a 
low of 6516 cases in 1955, and congenital and late manifestations receded 
similarly. 

Nineteen hundred fifty-five was the year that the late Paul O'Leary, 
one of the leading dermatologists of his time, summed up the attitude of 
the medical profession generally when he dropped the phrase ''and Syph- 
ilology" from the "A.M. A. Archives of Dermatology and Syphilology," of 
which he was editor. 

Syphilology was also de-emphasized in the curricula of medical schools 
throughout the country ; and thousands of young doctors came to gradua- 
tion without ever having probed the depths of the meaning behind Sir 
William Osier's famous predication that: "To know syphilis is to know 
medicine." 

The Board of Commissioners of the Joint Commission on Accreditation 
of Hospitals dropped routine admission serologic tests for syphilis as a 
requirement for hospital accreditation on January 28, 1956; and many 
authorities began to proclaim the required premarital blood test a useless 
relic. 

Federal venereal disease control appropriations, which had exceeded 
$17,000,000 annually, also were reduced in 1955 to a low of $3,000,000. 
(Although I might add that we were spending at least ten times that much 
on institutional care of paretics, and in fact, still are.) At the same time, 
state and local appropriations for venereal disease control dropped almost 
out of sight. 

The Rude Awakening 

There were some who were not totally enchanted by the promise of 
penicillin. Early in 1956, the Joint Statement of the Association of State 
and Territorial Health Officers, the American Venereal Disease Association, 
and the American Social Health Association took the general overoptimism 
to task and, although that was the year when reported infectious syphilis 
had reached its lowest level, this group hinted strongly that the trend 
might not continue. And they were proved right. 



Role of Public Health and Private Medicine in Syphilis 575 

In 1957, 6250 cases of infectious syphilis were reported. Six thousand 
six hundred were reported in 1958; 8100 in 1959; and so on, until in 1962 
more than 20,000 cases were reported. 

Private Patients Were Lost to Epidemiologic Study 

Now I want to go back and quote the J. A.M. A. editorial to which I 
alluded earlier, because I believe it makes a very valid assertion. It said this: 

*The successful control of syphilis between 1936 and 1946 . . . was 
the result of treatment of acute syphilis in public and university clinic 
hospitals, application of epidemiologic methods to investigation of con- 
tacts, case-finding, widespread serologic testing, etc. . . . (I'm still quoting) 
Up until 1946, the financial burden of prolonged chemotherapy, and the 
attendant inconveniences, technical difficulties, and complications led to 
mass treatment in public clinics and little in the private physician^ s office^' 
(in other words, to paraphrase this, treatment and follow-up of syphilis at 
that time was so troublesome that the average private physician didn't 
want to bother with it, so he channeled most of the syphilis patients to 
public health facilities, where they were not only treated, but followed, 
and also interviewed thoroughly for their contacts. The editorial continues) 
"but when penicillin became generally available, its ease of administration 
and need for few injections moved the treatment into the hands of the 
practicing physician and his office nurse . . . (and I'm still quoting) There- 
fore, it may be said that, as the patient moved into the physician's office 
for treatment, he was lost to epidemiologic control or case-finding" (end 
of quote). 

Actually, for a while, however, most of us in public health did not 
fully comprehend the significance of the phenomenon which is described 
here. 

It is true that as reported cases of infectious syphilis began to increase, 
particularly in the lower age brackets, and in the upper classes of society, 
control appropriations also came to be increased, with the result that badly 
depleted public health staffs were supplemented with new people of the 
highest quality obtainable from colleges and universities throughout the 
country, and additionally trained in the latest techniques of venereal 
disease epidemiology. And so, the full light of modern epidemiology was 
thrown on almost all the cases treated in public clinics. 

Public health people, however, were aware that a number, and perhaps 
a large number of infected persons were being treated privately, and that 
few of these were being interviewed adequately for contacts; but many 
felt, for a long time, that a sufficient percentage might somehow be brought 
into public clinics so that the number lost to epidemiology would be 
insignificant to the total picture. 

But it took most of us a long time to comprehend fully that, for a 
number of reasons, we were living in a fool's paradise. The truth was that 
we were doing little more than scratching the surface of epidemiology. To 



576 William J. Brown 

say that many infected persons were slipping through the epidemiologic 
net is to make a gross understatement. It is hardly an exaggeration to say 
that most were. 

What were some of the reasons for this? Well, for one thing, a genera- 
tion of physicians had gone into private practice, most of whom, for the 
reasons previously mentioned, had never seen a syphilitic lesion. And 
7000 more were, and are, being graduated annually who have never been 
exposed to more than a scant few hours of syphilology. That they were 
not prepared for syphilis was not their fault. In fact, the blame could not 
be laid on anybody's doorstep. It was simply a phenomenon of the times. 
Nevertheless, to literally thousands of these physicians came literally 
thousands of syphilitics — but quietly and covertly, a case here and there, 
because indiscriminate sexual behavior is seldom accompanied by fanfare. 

With what results? 

In many cases, syphilis was not deliberately excluded from differential 
diagnosis; it was just not even considered as a possibility; and the case was 
often diagnosed as an allergy or some other benign dermatosis, and was 
treated accordingly. 

Moreover, in many cases, when a reactive serologic test for syphilis 
was discovered by one means or another, there was often a tendency to 
interpret the serology as a biologic false-positive reaction. In such cases, 
even if '^insurance" therapy was adrninistered, the patient usually was lost 
to epidemiology. 

This situation was not, of course, etiologically responsible for the 
continuing increase of syphilis; but gradually, it became apparent to many 
persons in public health that, as long as it continued, there was little hope 
for the control of the disease, to say nothing of eradication. 

Recognition of the Need for Cooperation Between Public Health and 
Private Medicine 

Representatives of health departments around the country began to 
follow up reports of infectious syphilis morbidity, asking whether the 
patient had had an epidemiologic work-up, and if not whether a health 
department epidemiologist might have the physician's permission to do 
one. And to the surprise of many skeptics, such permission was often 
granted. 

Then a number of health departments — first a few, then many^began 
to check reactive laboratory reports with the submitting physician to 
inquire whether a diagnosis had been made, and whether the case had been 
reported. The success of all this activity is indicated by the following: 

Between 1959 and 1962 the number of individual private physicians 
reporting primary and secondary syphilis throughout the country increased 
by 75 per cent; and the total of private physicians reporting cases in 1962 
numbered about 3900. 

Over the same period, of the total cases actually reported, 50 per cent 



Role of Public Health and Pkivate Medicine in Syphilis 577 

were interviewed for contacts in 1959 and this figure increased to 81 per 
cent in 1962. 

Moreover, with respect to the thoroughness of the interview, of those 
interviewed in 1959, only 41.4 per cent were seen by the interviewer more 
than once; but in 1962, 70.9 per cent of these private patients were seen 
on two or more occasions by the interviewing epidemiologist. The results 
of this improvement are reflected m the fact that in 1959 only 30.6 per cent 
of these private patients disclosed either the source of their infection or 
someone to whom they transmitted it. By 1962, this figure had risen to 
53.2 per cent. 

In fact, the value of this kind of cooperation was demonstrated so 
conclusively that the Surgeon General's Special Task Force last year was 
convinced that, if the same kind of activity was carried out universally, 
along with a suitable public and professional education program, it might 
be entirely possible to eradicate syphilis. 

Recognizing, however, that a much more accurate index of the actual 
incidence of syphilis was needed, the American Medical Association, the 
National Medical Association and the American Osteopathic Association 
all cooperated with the American Social Health Association in a joint 
nationwide morbidity survey, the results of which were released in April, 
1963. 

They queried 183,000 physicians in all, and received an astounding 
response from 131,000. Probably the most important finding was that, for 
every privately treated case of infectious syphilis identified and reported, 
approximately nine cases had been identified and treated privately and not 
reported. This means that while in 1962, 20,000 cases of infectious syphilis 
were reported, of which the techniques of epidemiology were applied to 
about 16 or 17 thousand, the truth is that an additional 49,000 or so cases 
were treated privately and not reported. And, considering the annual level 
of reported early latent syphilis, the actual incidence of syphilis must now 
be something in excess of 120,000 cases. 

Yet every case of infectious syphilis, as every case of typhoid, polio, 
plague or the smallpox, is important from the standpoint of eradication. 
To quote again from the same J. A.M. A. editorial I mentioned earlier, 'Tn 
the overall control and eradication of venereal disease, treatment is hardly 
more than secondary to case-finding and investigation of contacts." 

To be Eradicated, Syphilis Must be Labeled Intolerable 

We have asked ourselves many times why it is that the average 
doctor, having found a case of typhoid, polio, plague or smallpox, almost 
couldn't get to the telephone fast enough to alert the Commissioner of 
Health. Yet, the same physician will not get excited about the presence of 
syphilis. And we have come to this conclusion : that infectious diseases can 
be sorted rather neatly into two categories: tolerable and intolerable; and 
that, to be eradicated, a disease must be moved into the mtolerable cate- 



578 William J. Brown 

gory and stay there. Although intolerable diseases are introduced into the 
country occasionally, they are always re-eradicated to the last trace, 
regardless of cost; whereas, tolerable diseases, on the other hand, are 
"controlled" at so-called "tolerable" levels. 

In fact, we have postulated a law of public health relating to the 
control of tolerable diseases, to-wit: "As a disease control program ap- 
proaches the end-point of eradication, it is the program rather than the 
disease which is the more likely to be eradicated." After that, of course, 
the disease simply gets out of control again and begins another cycle. And 
this, of course, is precisely what happened to syphilis in the mid '50's. 

I wish I could tell you why certain diseases enjoy this status of intol- 
erability while others do not. It's a thing which is difficult to pin down, 
but I'm sure that both public and professional education, associated ideas, 
public images, etc., have a lot to do with it. 

Probably another important factor is that, while most influential 
persons have some personal fear of these other dread diseases, few will 
admit to themselves that they might ever contract syphilis. Perhaps it is 
an unfortunate thing for the eradication of syphilis that it is not contracted 
from door handles, drinking fountains and toilet seats as in popular legend. 
In fact, one health educator recently suggested facetiously, but with a 
grain of truth, that if a virulent T. pallidum could be demjonstrated in a 
can of tuna fish, the eradication of syphilis might be well on its way. 

We talk about dread diseases, and plague is about as dread as they 
come; yet if I'm not mistaken, for every person who died from plague in 
the United States last year, 1000 died from syphilis. 

Perhaps you've noticed a difference in terminology about diseases. We 
talk about a smallpox scare, a typhoid scare, a plague scare or a polio 
scare, but never about a syphilis scare. We occasionally talk about a 
syphilis outbreak, but we seldom even go so far as to use the term syphilis 
epidemic. Probably one of the reasons for this is that, far from having 
reached a status of intolerability, syphilis has barely achieved a status 
even of visibility. 

I feel that many physicians are probably still correct when they say 
they haven't seen a case of early syphilis in 20 years. A few physicians are 
seeing a considerable number of cases, but the bulk of the cases are sparsely 
scattered. And because of the overall public and professional attitude 
toward syphilis, when a case is encountered, there is a tendency to consider 
it more of a curiosity than a cause for alarm; and until recently, there has 
seemed to be little urgency in reporting it, or in working it up epidemi- 
ologically. 

But somewhere along the line, this attitude is going to have to change; 
and I sincerely hope it will happen while penicillin is still effective; and 
how long that will be is anybody's guess. 

However, I think that it can be done through education, both public 
and professional — that is, through mass public awareness programs — 



Role of Public Health and Private Medicine in Syphilis 579 

through the introduction of material on venereal disease in grade and 
secondary school curricula — through the re-introduction of syphilis at 
appropriate places in the medical school curriculum — and through an 
exchange of information and discussion of venereal disease among profes- 
sionals. 

Education and Epidemiology Are Necessary 

Quite a bit of this sort of activity is being fostered by public health 
people now, and I hope more will be. A number of good materials and 
techniques have been developed for public education; and also some very 
good new educational items have been made available to medical schools 
and professional societies, and more are on their way. 

But recognizing the great need for epidemiology, a large part of 
venereal disease control resources available to public health are continuing 
to be channeled into shoe-leather epidemiology. The Public Health Service, 
for example, is continuing to train a large force of specialized nonmedical 
personnel in the techniques of syphilis epidemiology, and is making them 
available through state and local health departments wherever they are 
needed. And these are supplemented by several hundred state and local 
people — nurses, field workers, etc., also working full or part time in syphilis 
epidemiology. 

But if these techniques and resources are to be effective, they will 
have to be put to maximum use. 

The Pivot of an Eradication Program is the Doctor in Private Practice 

In a separate article in the March, 1963 issue of the Journal of the 
American Medical Association, to which I referred earlier. Dr. Kampmeier 
wrote : 

''If it is true that more patients are treated in doctors' offices than in 
public clinics, eradication of syphilis must have as its pivot the doctor in 
private practice, and will depend mainly upon cooperation of the practi- 
tioner with health authorities." 

This argument, we now know, is unimpeachable. But there probably 
are a number of ways of looking at this so-called ''cooperation." The 
suggestion usually made is that the private physician report all his cases 
and allow the public health epidemiologist to interview his patients. More 
often than not, this means today that, having learned of the diagnosis of 
an early case, a health department epidemiologist will approach the 
physician and seek permission to interview the patient — permission which 
may or may not be granted for any number of reasons. 

There probably are a number of other ways epidemiology might be 
handled, but the fact remains that in some way, for very practical reasons, 
the responsibility must he delegated by the physician, and if this has not so 
far been considered by professional committees on ethics, it well might be. 

While many private physicians do ask the patient about sexual 



580 William J. Brown 

contacts themselves, it is not realistic to ask or expect the average physician 
today to spare the extra hour and often more of time required for a thorough 
probe for contacts — a probe which often extends to several sessions and 
often discloses a surprising number of contacts when it is conducted by a 
trained interviewer. And the search for these contacts, which may extend 
over several states and countries, definitely is beyond the scope of the busy 
physician. So to expect the private physician to bear the active burden of 
epidemiology is simply not realistic, although under the circumstances he 
must bear the moral burden. 

The idea which has worked and worked well for several thousands of 
physicians is for the physician to diagnose and treat, and then call the 
public health epidemiologist by telephone to report the case and request 
him to interview the patient as soon as possible. 

And where this works best, you could not say that the physician 
allows the epidemiologist to interview his patient. The fact is that many a 
private physician now takes the public health responsibility by the horns, 
so to speak, and insists that a qualified public health epidemiologist be 
made available to perform this necessary function. And this is the idea 
which we must promote successfully if we are to see syphilis eradicated. 

We now know beyond doubt that, insofar as treatment in public 
clinics is concerned, the medically indigent will probably never again 
constitute a critical proportion of patients with new syphilis. As long as 
we have penicillin, and as long as this drug remains effective, the bulk of 
syphilis will be treated privately. 

Now let me summarize rapidly and then conclude. First, syphilis will 
have to be recognized generally by the medical profession as the serious 
and intolerable disease which it is, and every new case will have to be 
considered a cause for alarm. 

Secondly, if syphilis is to be eradicated, the physician will have to 
make a decision, either to employ and train his own epidemiologic staff, at 
whatever cost and probable inefficiency, or to call on the public health 
epidemiologic assistant as he would call on the services of any other 
professional consultant. In either case, part of the job of treating the 
patient will be to prepare him to meet the syphilis epidemiologist as he 
would prepare him to meet any other specialist. 

But to do this, he must have confidence in this third party and his 
method of operation. The possibility of violation of the privileged physician- 
patient relationship cannot excuse the neglect of epidemiology any more 
than it can excuse failure to refer any patient to any other specialist when 
the need for one is indicated. If, for any reason, the doctor or his professional 
associates feel that the professional relationship is in danger of jeopardy 
through existent public health practices with relation to syphilis, there is 
only one thing to be done. That is to get together with the public health 
authority and work out ways of operating so that it will not be in jeopardy. 



Role of Public Health and Private Medicine in Syphilis 581 

But I seriously doubt that such a danger exists in most health jurisdictions 
in the country. 

Syphilis is a Disease Which Should be Easy to Eradicate with the Tools 
We Have Today! 

That syphilis is not only surviving but flourishing in its present 
proportions is a fact in which none of us can take pride, and in which we 
must all, as responsible citizens, be alarmed. 

If we want to eradicate syphilis, we can do it, and with our present 
resources; but to do it, we will all have to work together — and I mean really 
together. 

In closing, I would like to say that I for one would be willing to see 
the private physician diagnose and treat all the syphilis, and let public 
health attend exclusively to the epidemiology; to me this is the only 
solution which really makes sense. 

Speaking frankly, as well as practically, I believe the effort to eradicate 
syphilis can be rewarding in many ways. The American pubUc can be 
nothing but grateful to American medicine for having made that effort. 

In dedicating himself to the eradication of syphilis, the private physi- 
cian — both as a professional and as a citizen — has everything to gain and 
nothing to lose. 

Communicable Disease Center 
U. S. Public Health Service 
Atlanta, Georgia 30333 



what the American Medical Association 
Is Doing About SyphiHs 



CHARLES L. HUDSON, M.D.* 



The American Medical Association has been alert to syphilis 
for a great number of years and, cognizant of its bearing on our national 
well-being, has waged continuous war on it. As early as the year 1874 the 
House of Delegates of the American Medical Association approved appoint- 
ment of a committee to report on the most feasible plan for securing 
legislation to prevent the spread of syphilis. In June of 1876 President 
Marion J. Sims delivered an address on the status of the disease which the 
Association printed and distributed to put the public spotlight on syphilis. 
In 1899 it appointed a special committee to attend the International 
Conference for the Prevention of Syphilis, further recommending that a 
report be made on the best means of preventing the spread of syphilis. 

The Association in 1903 made these resolutions: (1) To bring propa- 
ganda into the different states looking toward the proper recognition of 
dangers from venereal diseases; (2) to arrange for a national meeting to be 
held under the auspices of the Association for the prophylaxis of venereal 
diseases; and (3) to stimulate study and uniform knowledge on the subject 
of prophylaxis of venereal disease. 

An important resolution adopted by the Association in 1917 stated 
that it commends the following as the basis for a program of civil activities : 

1. That sexual continence is compatible with health and is the best 
prevention of venereal infections. 

2. That steps be taken toward the prevention of venereal infections 
through prevention of prostitution, and by the provision of suitable recrea- 
tional facilities, the control of alcoholic drinks, and other effective con- 
structive measures. 

3. That plans be adopted for centralized control of venereal infections 
through special divisions of the proper health and medical services. 



Read at, Syphilis: A Symposium, Vanderbilt University School of Medicine, Nashville, 
Tennessee, May 17-18, 1963. 

* Board of Trustees, American Medical Association ; Associate Professor of Medicine, 
Cleveland Clinic Educational Foundation ; Associate Clinical Professor of Medi- 
cine, Western Reserve University School of Medicine, Cleveland, Ohio 

583 



584 Charles L. Hudson 

4. That the hospitals and dispensaries be encouraged to increase their 
facilities for early treatment and follow-up service for venereal diseases as 
a measure of national efficiency. 

5. That the members of the medical profession be urged to make every 
effort to promote public opinion in support of measures instituted in 
accordance with these principles of action in the control of venereal diseases. 

These were early efforts in combating the inroads being made by 
syphilis in American society. 

In 1942, the Association called for the elimination of commercialized 
prostitution, and warned that a whole series of medical treatments given 
by physicians to prostitutes constituted unethical practice in the medical 
profession. And, most lately, it has cooperated with the American Social 
Health Association in the extensive mailing of a comprehensive question- 
naire to private practitioners all over the country in an effort to determine 
by survey what the status of syphilis in our country is today. This knowl- 
edge is now available to the Public Health Service for evaluation and use 
in administering a new program directed at the eradication of syphilis. 

In the area of medical education, the Association early recognized the 
need for more comprehensive study of the subject of syphilis and recom- 
mended, in 1921, ''rapid extension of teaching facilities for the use of 
medical students whereby the knowledge of the medical, social and public 
health aspects of these diseases may be taught by actual clinical contact 
with patients under the direction of qualified teachers." 

In this area, too, it asked its Section on Dermatology in 1921 to 
ascertain the actual history of syphilis, and to make this history available 
to students of medicine. 

And in 1951, the Association, in its position as a watchdog of medical 
education in the United States, discovered ''deficient teaching programs in 
dermatology and syphilology in some medical schools," and had its Council 
on Medical Education and Hospitals give proper attention to correct this 
flaw. 

Additionally, a full-fledged educational program is continuously being 
carried on under American Medical Association auspices through numerous 
sessions at both Clinical and Annual meetings, devoted specifically to the 
subject of venereal diseases and syphilology. At the coming Annual meeting 
June 16 to 20, in Atlantic City, there will be a symposium on venereal 
diseases. 

Articles such as the one which appeared in a recent issue of the Journal 
of the A.M. A., by Doctor R. H. Kampmeier, are constantly appearing in 
A.M. A. publications to keep the subject before the eyes of physicians 
everywhere. 

At all opportunities, the Association's officials have urged local medical 
societies to take active cognizance of the war on syphilis and to lend 
support to the findings of the HEW Special Task Force on Syphilis. 

The Special Task Force in reporting to the Surgeon General of the 
United States Public Health Service has urged the setting of a six-point, 



What the American Medical Association Is Doing About Syphilis 585 

ten-year goal for the elimination of syphilis as a public health hazard. The 
recommended points are : 

1. An intensive national effort providing for at least two visits a year 
by a qualified health worker to the country's 100,000 general practitioners 
and one visit per year to the remaining 130,000 physicians. 

2. Establishment of a program to insure that all blood processing 
laboratories report to health departments all positive specimens by name 
of patient. 

3. Intensification and extension of current interview-investigation 
services to cover all infectious syphilis cases. 

4. Development of a comprehensive and dynamic education program 
for professional workers and the general public. 

5. Continuation of research in syphiUs immunology, therapy and 
laboratory procedure and greater expansion of research in adolescent and 
young adult sex behavior. 

6. Unstinted support of the program by Federal, State and local 
governments even after the reported number of syphilis cases begin to 
decline. 

Reliable estimates indicate that infectious syphilis (reported and unre- 
ported) occurs in the United States at a rate of 60,000 cases a year, while 
the number of gonorrhea cases is estimated at one million. The total of 
20,084 reported cases of infectious syphiUs in 1962 was 7 per cent above 
the 1961 total. 

People under 24 accounted for 45.7 per cent of reported syphilis cases 
and 55 per cent of reported gonorrhea cases. The 15-19 age group had the 
highest increase in incidence of infectious syphilis — 10 per cent. 

Nineteen states and 44 cities reported that more than 20 per cent of 
males named males as their sex partners. 

Thirty-three states and 73 cities said prostitution was an increasing 
cause of venereal disease. 

Concern must be felt in view of these alarming statistics. What is our 
present responsibility in this battle? We feel that private practitioners 
have the primary responsibility in our fight against syphilis. As Doctor 
Kampmeier states, they * 'still hold the key to eradication of syphilis 
because they treat more syphilitic patients in the office than are treated 
in public clinics." Case finding and the investigation of contact, methods 
long used by public health agencies, if adopted by the private practitioner 
might well prove to be the answer we are seeking. 

Because Doctor Kampmeier, a physician well-published in this field, 
has had the foresight to wave a flag of warning in the face of many who 
have felt that syphilis, this bane of so many civilizations in history past, 
had been controlled, we tender him our collective gratitude, in the interest 
of national health, for his vigilance in this most important area. 

Cleveland Clinic 
2020 East 93rd Street 
Cleveland 6, Ohio 



Syphilis Through the Ages 



WILLIAM L. FLEMING, M.D. 



This presentation will be focused on the origin of syphilis, on 
the development of our knowledge of this disease, and on what we know 
of factors affecting the incidence and prevalence of syphilis since the fif- 
teenth century, in order to direct attention to the aspects of epidemiology 
most relevant to today's problems. 

THE ORIGIN OF SYPHILIS 

The controversy over whether syphilis existed in Europe prior to the 
return of the first expedition of Columbus from the Americas to Spain in 
1493 will probably never be resolved. Consequently, it seems best to 
emphasize what seem to be the salient facts at the outset of this discussion. 

There was unquestionably an epidemic of syphilis in a very severe 
form which swept over Europe and spread to other countries and continents 
in the latter part of the fifteenth and early part of the sixteenth centuries. 
Evidence of the pre-Columbian existence of syphilis in Europe has been 
very carefully examined mainly by the search of literature of various kinds 
for descriptions of the disease and by examining pre-Columbian bones for 
gross changes characteristic of syphilis. Suffice it to say that, while there 
is some disagreement as to the findings, the paucity of even alleged 
European pre-Columbian literary and osseous evidence of syphiUs is strik- 
ing. On the other hand, the abundant evidence that syphilis existed in the 
Americas at the time of Columbus' first voyage and the abundant evidence 
of the existence of pre-Columbian syphilitic bones in the Americas is equally 
striking. Consequently, the author is led to the conclusion that, while 
yaws and perhaps other spirochetal diseases even more closely related to 
syphilis undoubtedly existed in other parts of the world, the disease 
syphilis as we know it probably first appeared in Europe in the fifteenth 
century — possibly by spontaneous mutation of a spirochete already present 



Read at, Syphilis: A Symposium, Vanderbilt University School of Medicine, Nashville, 

Tennessee, May 17-18, 1963 
* Chairman, Department of Preventive Medicine, School of Medicine, University of 

North CaroUna, Chapel Hill, N. C. 

587 



588 



William L. Fleming 



Figure 1. 
(Jeanselme.)* 



oCon paoilcgioimpcnai 




Kl 



5rractado(:6rraclJiwI 

fcrprmmorqucDulgarmcn 

(cn)j£fpanar£}ltamado 

bub3oofuco:dcijado 

cndolpicalDctodcHi 

loofjncoo^ailbo 

na:fccbopozru]r 



l\ yj^ 




Title page from Dias de Isla's Treatise Against the Serpentine Disease. 



— but probably by introduction from without, and most likely from the 
Americas. 

It has not been possible for the author (or for most of those writing 
on the subject) to examine original references and sources of evidence. 
Most of the historical information in this paper comes from Pusey,^^ 
perhaps the most authoritative American historian of syphilis, who quotes 
not only early sources but such medical historians interested in this disease 
as Sudhoff, Block, Haustein, Williams and the latter's translation of 
Montejo. It has also been possible in the preparation of this paper to 
examine some of the writings of John Hunter,^ Ricord^ and Fournier,^* 
eminent clinicians of the eighteenth and nineteenth centuries, who added 
so much to our clinical knowledge of the disease, as well as publications 
of Buret,^ a French nineteenth century historian of syphilis. 

Pusey^* mentions the documentation given by some of the opponents 
of the American origin of syphilis professing to indicate that the great 

* Figures 1 to 14 inclusive are from Pusey, W. A.: The History and Epidemiology 
of Syphilis. Springfield, 111., C. C Thomas, 1933. 



Syphilis Through the Ages 



589 



epidemic in Europe started a few years before the return of Columbus, but 
feels this evidence is unconvincing. Pusey feels that perhaps the best 
documentation of the beginning of the syphilis epidemic is provided by 
Montejo y Robledo, Spanish army surgeon, in a paper presented to the 
fourth Congreso Internacional de Americanistas at Madrid in 1882, which 
was publicized by Iwan Bloch in 1901. Williams, Rice and Renato-Lacayo^^ 
examined Montejo's article and translated many of its passages. Montejo 
examined early Spanish chronicles of America. Oviedo^* in "Historia gen- 
eral y natural de las Indias" and Las Casas^^ (whose father accompanied 
Columbus on the second voyage) provide particularly pertinent material 
as do other early historians^* of Spanish America — such as Pane, Saligua, 
and Hernandez— as to the existence of syphilis in the Americas and as to 
its appearance as a new disease in Spain after the return of Columbus. 
Perhaps the most convincing is Dias de Isla.^* Montejo examined his book 
'Treatise on the Serpentine Malady . . ." (Fig. 1), written between 1510 
and 1520 and published in 1539, and even examined the original manu- 
script in the National Library of Madrid which contained some significant 
passages not in the published work. Dias de Isla was in practice in Barcelona 
in 1493 when Columbus' first expedition returned. Dias states very clearly 
that syphilis was unknown prior to 1493 and that it was introduced into 
Barcelona by the men of Columbus' vessels on thoir return from Espafiola. 



te BAGAoe 




Figure 2. The Impedimenta (of the army). Triumph of the high and mighty 
Dame Syphilis, Queen of the Fountain of Love (Le Triumphe de treshaulte et puissante 
Dame Verolle). Lyons, 1539 (Anon.) (Jeanselme.) 



590 



William L. Fleming 




Figure 3. 
(Bloch.) 



Syphilis, 1496, Albert Diirer. 



Dias called syphilis the '' Disease of the Isle of Espanola." Many of the 
crews of the vessels are said to have been infected, including one of the 
pilots. Dias treated several. Pusey quotes^^ a passage from Dias as follows: 

It has pleased divine justice to give and send down upon us unknown 
afflictions, never seen nor recognized nor found in medical books, such as 
this serpentine disease ... at the time that the Admiral don Xristoual 
Colon arrived in Spain, the CathoUc sovereigns were in the city of Barcel- 
ona. And when they went to give them an account of their voyage and of 
what they had discovered immediately the city began to be infected and the 
aforesaid disease spread as was seen later on through long experience. ... 
In the following year of 1494 the most Christian King Charles of France 
who was then reigning having gathered a great army passed into Italy. 
And at the time that he entered the country with his host many Spaniards 



Syphilis Through the Ages 



591 



infected with this disease were in it and at once the camp began to be in- 
fected with the aforesaid malady and the French, as they did not know 
what it was, thought it came from the atmosphere of the region. The 
French called it the disease of Naples. 

As Dias has outlined, King Charles VIII of France with an army 
composed of mercenaries — many from other countries — invaded Italy in 
the autumn of 1494 to seize the throne of Naples. There was little fighting, 
but Spanish soldiers sent to help protect Naples, together with other 
Spanish mercenaries in the French army, may have introduced syphilis. 
Armies of that day were accompanied by many female camp followers so 
the campaign, because of the absence of fighting, was more than usual a 
march of debauchery. A plague which most contemporary records attribute 
to syphilis attacked this army and by the spring of 1495 had forced its 
retreat from Italy. (Sudhoff^* almost alone among historians denies this 
epidemic was due to syphilis and attributes it to typhoid or paratyphoid.) 
An old woodcut of 1539 (Fig. 2) pictures the impedimenta of an army 



1 


/C\\=/^ 


^^^%\ 




M 


^^^i 


IJ-^T^ 


^^^ra 


^/^\y^^^-4^^ 



Figure 4. Title page from Bartholomew Steber's Syphilis, 1497 or 1498. Probably 
the earliest illustration of syphilis. (Bloch.) 



592 



William L. Fleming 




Figure 5. Title page from Grunpeck's Tractatus de pestilentiale: Scorra sive malady 
Franzos, 1496(?). (Jeanselme.) 



(possibly that of Charles VIII) as the ^'Triumph of the high and mighty 
Dame Syphilis, Queen of the Fountain of Love." Again, most contem 
porary records attribute the beginning of the epidemic in Europe to th 
dispersal of the mercenaries of Charles VIIFs army over Eur(^pe. 

Syphilis in local chronicles^ ^ is said to have appeared in France 
Germany and Switzerland in 1495, in Holland and Greece in 1496, ii 
England and Scotland in 1497, in Hungary and Russia in 1499. Agair 
while some have claimed references to syphilis in ancient Chinese literatun 
Pusey quotes^* Dohi of the University of Tokyo, whose studies indicate thi 
spread of syphihs to Asia only after the epidemic in Europe and after visiii 
of Portuguese explorers. Everywhere the disease was regarded as new ao 
names for it appeared which attempted to shift the responsibility for it t 
others. 'The Italians called it the Spanish or French disease; the Frenc 
called it the Italian or Neopolitan disease ; the English called it the Frenc 
disease; the Russians called it the Polish disease; the Turks called it tl 



Syphilis Through the Ages 



593 



French disease . . . [and as previously mentioned] the first Spaniards who 
recognized the disease called it the disease of Espanola. . . ."^'' 

Publications regarding syphilis soon appeared in Europe. The first is 
accredited to Durer in 1496 (Fig. 3). Steber^^ in 1497 or 1498 is credited 
with the first illustration of a syphilitic, although Grunspeck's illustration^* 
may have appeared in 1496 (Figs. 4 and 5). 

Another evidence cited in favor of syphilis' having been a new disease 
in Europe was its severity. For the first 50 years or so secondary syphilis 
tended to be accompanied by severe systemic symptoms which not too 
infrequently led to death. 

In addition to the literature, the search for characteristic gross lesions 
of syphilis such as this skulP* (Fig. 6) from Peru by such authorities as 
Elliott Smith, Williams and Means has turned up many such pre-Columbian 
bones in both North and South America. There has been some dispute 
about a few European pre-Columbian bones, but their number is remark- 
ably few and many authorities accept none as being both definitely pre- 
Columbian and syphilitic. 



^- 




4: 



Figure 6. Ancient syphilitic skull from Paracas, Peru. (American Museum of 
Natural History — Williams.) 



594 



William L. Fleming 



DEVELOPMENT OF KNOWLEDGE OF SYPHILIS 

Understanding of the clinical characteristics of syphilis developed 
rapidly in the sixteenth century with the preoccupation of medical circles 
with the great epidemic as evidenced by the more than 40 authors of 
treatises on the subject. Fracastor, physician-author, who developed a 
theory of the microbic origin of infections, provided the name for the 
disease in his poem ''Syphilis sive Morbus Gallicus" published in 1530 
(Fig. 7). The importance of sexual intercourse in its transmission was 
recognized from the first, although poor hygiene made extragenital trans- 
mission relatively common. Congenital syphilis was soon recognized. Syph- 
ilis was fairly clearly differentiated from gonorrhea at first, but soon became 
confused with gonorrhea. The differential characteristics of the chancre 
were recognized and many secondary and late manifestations were 
described.^-^ 



HIIRONYMI FRACASTORII 

STPfirLIS 

SIVE MORBVS GALLICV^ 

yermtt M D X X X^mn^t hm$lf9l 



Figure 7. Title page from Fracastor's Syphilis Sive Morbus Gallicus. Actual siz« 
5M X S}4. (Crerar Library.) 



Syphilis Through the Ages 



595 



"«r«--t3r 










T A M S T f. II 1>A M 



/ ' \: < 



Figure 8. The Pox. Treatment of the venereal diseases hy inunctions and inhalations. 
Title page from Stephen Blankaart's Venus belegerten Ontset, Amsterdam, 1684. (Jean- 
selme.) 



596 



William L. Fleming 




^OVR\. 

PLAfsiiK 
FOLIEL 

Figure 9. Fumigation (sweating treatment of syphilis). From the collection of 
engravings by Jacques Laniet of famous proverbs, Paris, 1659-1663. (Jeanselme.) 

Not shown are interesting comments appearing at the bottom of the woodcut, 
which (translated) are as follows: 



For one small pleasure I 

suffer a thousand misfortunes. 

I exchange one winter for two 
miserable summers. 



I sweat all over my body and 
my jaw trembles. 

I do not believe I will 

ever see the end of my troubles. 



Paracelsus is given credit for the introduction of mercury, but mercury 
was so commonly used in the treatment of skin disorders that it must have 
been tried empirically by many independently. Fever or sweating treatment 
was much in vogue as was treatment by mercury and other inunctions and 
inhalations, as is shown in these seventeenth century pictures (Figs. 8 and 
9). Development of knowledge of syphilis continued rapidly during the 
seventeenth and eighteenth centuries but received a considerable set-back 
when John Hunter's self -inoculation experiment^ led him to again consider 
syphilis and gonorrhea the same disease. The nineteenth century brought 
the great French syphilographers, perhaps chief among whom were Ricord 
and Fournier. Ricord again separated syphilis and gonorrhea. Ricord (Fig. 
10), renowned for his wit, was firmly opposed to the theory of the American 
origin of syphilis, as is shown by his statement^^ that the first sentence of 
the Bible really should be: ^^In the beginning, God created the heavens, 
the earth, man and venereal diseases," meaning that all venereal diseases 
had existed everywhere since the dawn of time. Ricord showed his close 
study of the disease by such aphorisms as ''the bubo is not only the faithfu 
companion of chancre but also a posthumous witness that long survives 
it,'''^'' and his impression of the seriousness of the disease by such statement.' 
as "the pox is a pitiless creditor and grants grace to no one."^'' Olive: 



Syphilis Through the Ages 



597 




Figure 10. Phillippe Kicord (1799-1889). 




Figure 11. Jean-Alfred Foumier (1832-1914). 



598 



William L. Fleming 



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Figure 12. Tablet to Fritz Schaudinn (1871-1906). 




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Figure 13. Erich Hoffman (1868-1959). 



Syphilis Through the Ages 



599 





Figure 14. August von Wassermann (1866-1925). 

Wendell Holmes called Ricord ''the Voltaire of pelvic literature — a skeptic 
as to the morality of the race in general, who would have submitted Diana 
to treatment with his mineral specifics and ordered a course of blue pills 
for the vestal virgins. "^^ Fournier's (Fig. 11) knowledge of clinical syphilis 
(in spite of the absence of laboratory tests) was almost complete, including 
the relation of so-called parasyphilis, paresis and tabes. He systematized 
prolonged treatment with mercury and the iodides and in his remarkably 
perceptive book on ''Syphilis and Marriage"^^ showed that he possessed 
very good information on infectiousness in syphilis and did much to 
encourage physicians to help prevent the marriage of infectious or poten- 
tially infectious individuals since, as Dechambre quoted by Fournier^^ said : 
"the pox, like the daily bread, is divided between husband and wife." 

The early part of the twentieth century witnessed, as we know, in the 
short period of 1905-1910 the discovery of the causative agent by Schaudinn 
and Hoffman, the introduction of the complement fixation test by Wasser- 
mann, and the introduction of arsphenamine by Ehrlich in 1910 (Figs. 12, 
13 and 14). 



THE COURSE OF SYPHILIS IN THE WESTERN WORLD SINCE 1500 

It is difficult for us today to come up with reliable information about 
the prevalence of chronic diseases, and we have even less information about 



600 William L. Fleming 

the past. "Syphilization" of Europe and the Western World proceeded 
rapidly after 1500. Prostitution would seem to have been a very important 
factor in its spread — and a much more important factor than today. 
Social factors operated as in the present age, and evidence from the 
literature, medical writings and history as to its relative frequency among 
upper social classes suggests much greater prevalence than today. Conse- 
quently, it is quite possible that syphilis had declined materially in fre- 
quency prior to the mid-nineteenth century. Nevertheless, we have chosen 
to focus on the prevalence of syphilis in the mid-nineteenth century, and 
on whether we have any evidence of a trend in the prevalence of syphilis 
between 1860 and 1910, a period of great social change but which preceded 
the advent of effective means of diagnosing and treating syphilis. 

Syphilis: 1860-1910 

There were serious attempts to estimate the prevalence of syphilis in 
the nineteenth century. Fournier and Erb^* are credited with estimating 
prevalence as 5 to 10 per cent based on use of history and clinical findings 
alone, and Neisser estimated the population of Berlin as being 12 per cent 
syphilitic, while Fournier estimated the population of Paris as being 15 per 
cent syphilitic.^ Since they could diagnose latent syphilis only by history, 
it is difficult to believe that the availability of a serologic test would not 
have resulted in much higher estimates. 

Haustein,^ Hinrichsen,^ and Siler^ accumulated information on the 
incidence and prevalence of syphilis and other venereal diseases in military 
personnel since they constituted one of the few groups in the 1860-1910 | 
period for which much information is available. Moore* examined these 
data to see if they could be used as indices of change in civilian populations ; 
of this period. These data are much more reliable in indicating changes 
within an army than in indicating differences between armies or in overall 
accuracy. 

Moore* constructed figures which show some of these data. The first 
of these (Fig. 15) provides information on the Prussian Army, indicating 
a change in incidence of all syphilis from rates of 7.5 to 9.7 in the 1876-1886 
period to 4 to 5.2 in 1910. In the British Army (Fig. 16) more accurate in- 
formation as to the incidence of primary and secondary syphilis was 
available and indicates a change from rates of 101.8 in 1890 to 20.4 in 
1910. Moore constructed a figure from Siler's data on the incidence of 
syphilis in the American Army (Fig. 17) which shows the upsurges con- 
nected with wars and the decline in the 1860-1910 period from rates of 70 
to 25. In another figure (Fig. 18) Moore brought together data from the 
major armies of the Western World showing that with a few exceptions 
there were sizable decreases in reported military incidence and prevalence 
in the 1860-1910 period. World War I caused a considerable upsurge in 
syphilis as shown by data from the French and Dutch armies (Fig. 19). 



Syphilis Through the Ages 



601 



PRUSSIAN 



* *«soft c^oncre {including primoryT, )+ syphilis, 

^ ^ . rote per lOOO strength 

' syphilis only 

«> — 0- strength of comnftand by 100,000 
e0.r ~~~"- - ^o data for these years 



\ 



86.1 
23.7 



SOURCE >Hausteifv 







u. 



Chontiroid and prmory Zj 
specificdlly grouped together 
1867-1869; not stated '. 
thereof teir. 






:::.:i:il, 



<i» 



Figure 15* 

_ * Figures 15 to 22 inclusive and Figure 25 are from Moore, J. E.: An evaluation of 
public health measures for the control of syphilis. Am. J. Syph., Gonor. & Ven. Dis. 
35: 101, 1951. 



602 



William L. Fleming 



jot. 8 



BRliri^i'^HMt {AT H 

PRIMARY AND SECONDARY C 
ftAT£,Pef^ iioob 

,1 SOURCE- Houstem 




\ No dota I9l4~t920 mclusive 
X,^...--^ (World War I ) 



^6.5 



Average strength of 
Command obout 100,000 



m <x> Qi m iji <h m ^ 



Figure 16 



Syphilis Through the Ages 



603 



teal 

1826 
l8Si 

»e46 Mfixleon War 



mi. 

^ »66 



CrvH War 



\m\ 



t8S>6 Spcifush- Afntrican War 
1901 Pl»<»p|Hrt« Insurrection 






19SI 

194.J WofJd War H 

i94« 



604 



William L. Fleming 



Trend of IZ Incidence in Major Armies 
1865-1913 
(Source- Haustein ) 



Years 
included 



% Decrease 



%lncrease 



Years 
included 



I870-I9II (42) 
1867-1908(42) 
1874-1913(40) 
1868-1912(45) 
1876-1913 (38) 
1865-1913(49) 
1887-1913(27) 
1867-1913 (47) 
1874-1913(40) 
1888-1910(22) 




LUiuidu \iusnsn 



(42) 1870-1911 
(22) 1889-1910 
(42) 1887-1908 



100 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 100 

Figure 18 



Crude as these indices are, they do suggest that there was a real 
decline in the incidence of syphilis in Western armies in 1860-1910, prob- 
ably reflecting also declines in the civilian populations of the Western 
World. As Moore^ pointed out, this decline can hardly be attributed in 
very significant measure to treatment or control measures. Mercury was 
the only treatment measure in use in this period which could have had any 
significant effect on infectiousness and there is little evidence that it was 
sufficiently effective and used widely enough to decrease the attack rate of 
syphilis. Similarly, there is no evidence that any specific control measures 
were important. 

We do know that during this period there were great social changes 
going on in the Western World. The full effect of the industrial revolution 
was beginning to be felt and the standard of living was rising rapidly. 
Along with this rise in the standard of living, public education improved 
correspondingly. We know that there has always been a very uneven 
distribution of syphilis in the population, with syphilis being generally 
inversely proportional in prevalence to educational and economic status. 
Moore ^ reproduced a figure (Fig. 20) which shows the relationship of 
syphilis mortality to socio-economic status in England. Also, as part of the 
explanation, Moore reproduced a figure (Fig. 21) from Kinsey's data which 
shows evidence on the amount of extramarital intercourse as related to 
educational level and occupational class. 



Syphilis Through the Ages 



605 



/ / 



\r 




/ years. / 

I • \/ 



Si 



INCIDENCE or L BEFORE,: 

DURING, AND AFTER j 

WORLD WAR I ! 

« • « Dutch krmi [ 

{NtutrallatltorlyE^ 

«^~* — ^ » FrertcN Army 

(combotQftt) 1 

"Prlmiify*' E ^ 



SOURCE- Houstein 



World War r 

i i I I I I I I I I i i ^ 

Figure 19 



606 



William L. Fleming 



I50i 
140 
130 
120 
110 
100 
90 ^ 
80 
70 
60 ^ 
50 
40 
30 
20 
10 



Wi ' Males 

I I = Females (married,by ^ 

husband's occupation) ^ 

nr - °^ . 

i 



I-. 



P 

is 



«4; 



intermediate 



m 



y/y 






^ 



% 

yk in 



Figure 20. Ratio of actual to 
expected deaths (syphilis, tabes, 
paresis and aneurysm) by social 
class, ages 20-65 years, England 
and Wales, 1930-1932. 



TOTAL EXTRA' MARITAL INTERCOURSE 



EDUCATIONAL 
LEVEt 



0-8 




9-12 



OCCUPATIONAL 
CLASS 



16.7. 




Figure 21. Extramarital intercourse, by educational level and occupational class. 
For single males of the age group 16-20. Relative lengths of bars compare mean fre- 
quencies for the groups. Note similarity of data based on educational levels and data 
based on occupational classes. (Kinsey et al.: Sexual Behavior in the Human Male.) 



The purpose of reviewing this material for the 1860-1910 period, which 
suggests a real decline in syphilis due to social factors rather than treatment 
or control program, is to point up the fact that social factors have profoundly 
affected the prevalence of this disease before and can do so again. Also, we 
should keep in mind that social factors do not remain the same. 

We should now examine what has happened to the incidence and 
prevalence of syphilis since 1910. 

Syphilis: 1910-1938 

This was the period after the introduction of effective arsenical treat- 
ment and of the serologic test and darkfield as tools in case finding. The 



Syphilis Through the Ages 



607 



Scandinavian countries with effective public treatment and control pro- 
grams reduced the attack rate of syphilis considerably (Fig. 22). In the 
United States the control program was weak except during World War I 
and probably did not have too much effect. 

In 1938 Vonderlehr and Usilton^o estimated that in the United States 
a person stood one chance in ten of acquiring syphilis before he died. The 
draftee survey of World War II furnished accurate information as to the 
prevalence of syphilis. Rates for positive serologic tests for syphilis in the 
draftee male age groups 18-40 (predominantly 21-35) were 1.8 per cent 



SWEDEN 

CASES OF VENEREAL DISEASE REPORTED 



6000 



4500 



3000 



1500 



1 1 


' ' ' A 


1 1 1 1 


1 1 1 1 

. SYPHILI, 


MM 










X 




\ 






,.,1 1 


1 1 1 1 


1 1 1 1 


1 1 1 1 


1 1 J 1 ,. 



1915 



1920 



1925 



1930 



1935 



400 



300 



NORWAY 

VENEREAL DISEASE 

CASE RATES PER 100,000 POPULATION 




1920 



1925 

Figure 22 



1930 1933 



608 



William L. Fleming 



CASES 



TOTAL I 
and 6.C. 


londn 

s 


500,000 


34,000 - 


475.000 


32.000 - 


450.000 


30.000 - 


425.000 


28.000 - 


400.000 


26.000 - 


375.000 


24.000 - 


350,000 


22.000 - 


325,000 


20.000 - 


300,000 


18.000 - 


275.000 


16.000 - 


250.000 


14.000 - 


225.000 


12,000 - 


200.000 


10,000 - 


175,000 


8.000 - 


150,000 


6.000 - 


125.000 


4.000 - 


100.000 


2,000 - 



77,007 



O Primary and Secondary SYPHILIS 
• All stages of SYPHILIS 
▲ GONORRHEA 




— I — 
1925 



CALENDAR YEARS— > 1920 1925 1930 1935 1940 1945 1950 1955 I960 

Figure 23. Reported cases of syphilis and gonorrhea in the United States. 



for white and 24.5 per cent for Negroes, or an average of 4.6 per cent." 
Extrapolating these figures for both sexes and all ages of the population of 
the United States, Parran and Vonderlehr^- estimated that 2.4 per cent of 
individuals of the country, or one in 42, had syphilis at a given time. There 
were important sectional differences, with rates for both whites and Negroes 
being highest in the South. 

Syphilis: 1938-1954 

In 1938 the Syphilis Control Program really got under way in the 
United States under Parran's leadership. The upsurge of syphiUs to be 
expected in World War II, on the basis of experience in all previous wars, 
was largely contained. The peak of reported primary and secondary 
syphilis cases was reached in 1947 and then a sharp decline in reported 
primary and secondary syphilis cases occurred, reaching the low point in 
1954. 



Syphilis Through the Ages 609 

Syphilis: 1954-1958 

During this period there was Httle overall change in reported primary 
and secondary syphilis cases. 

Syphilis: 1959-Present 

Following the low period of 1954-1958, reported primary and secondary 
cases rose sharply in 1959 and the upward trend has continued until the 
present. From the absolute low of 6251 cases of primary and secondary 
syphilis, or a rate of 4.1 in fiscal 1957, there has been a rise to 20,084 cases 
and a rate of 11 in fiscal 1962 (Figs. 23 and 24). 

Factors in Post-War Fall While few would doubt that the control 
program helped to bring the rate down after World War II, undoubtedly 
part of the decline would have occurred in any event following cessation 
of the war, as syphilis had declined following previous wars. 

Possible Important Factors in Recent Increase. Penicillin was intro- 
duced in the treatment of syphilis in 1943 and its use became general 



REPORTED SYPHILIS CASE RATE PER 100,000 POPULATION 
FISCAL YEARS 1941 - 1961 





Total 


Primary 


Prinxjry, 


Late and 




Fiscal 


Including 


and 


Secondary and 


Late 




Year 


Not Stated 


Secondary 


Early Latent 


Latent 


Congenital 


United States Civilians 


1941 


368.2 


51.7 


134.4 


153.9 


13.4 


1942 


363.4 


57.1 


145.1 


153.1 


12.8 


1943 


447.0 


63.8 


179.8 


195.7 


12.6 


1944 


367.9 


61.7 


158.5 


159.6 


10.7 


1945 


282.3 


60.5 


140.5 


111.8 


9.7 


1946 


271.7 


70.9 


151.6 


93.6 


9.0 


1947 


264.6 


75.6 


152.0 


86.5 


8.7 


1948 


234.7 


55.9 


123.8 


86.1 


9.2 


1949 


197.3 


37.1 


94.7 


83.3 


9.8 


1950 


154.2 


21.6 


65.1 


75.5 


9.0 


1951 


131.8 


12.1 


46.8 


71.1 


8.5 


1952 


110.8 


7.9 


33.1 


66.9 


6.1 


1953 


100.8 


6.2 


27.0 


64.7 


5.2 


1954 


87.5 


4.9 


20.8 


59.4 


4.6 


1955 


76.0 


4.1 


17.5 


52.7 


3.4 


1956 


77.1 


4.1 


16.3 


54.8 


3.4 


1957 


78.3 


3.8 


15.2 


58.1 


3.3 


1958 


68.5 


3.9 


13.7 


50.5 


2.8 


1959 


69.3 


4.7 


14.9 


50.1 


3.0 


1960 


68.0 


7.1 


16.6 


47.6 


2.6 


1961 


69.7 


10.4 


21.1 


45.0 


2.4 



Figure 24. (From VD Fact Sheets, 1961.") 



"1" William L. Fleming 

How Ooesi: Reach Medical Care i 

Previously untreated patients (July 1946- December 1947) 






Primary and Secondary 
21533 coses 



Early Lotent 
22047 coses 



Lote (all forms) 
175004 coses 



Patients' tnitiative 
:S§S5:SSj: Contact Investigation 



All other reasons 



Based on data from 16 States^ Chicago, St. Louis, and New York City 

Figure 25 

shortly after World War 11. Since arsenic-bismuth treatment was unsuited 
but penicillin was suited to the doctor's office, the diagnosis and treatment 
of syphilis has shifted from the public clinic to the private doctor's office — 
and to an extent we have only recently learned. The National Study of 
Venereal Disease Incidence^^ has recently shown that only a little more than 
10 per cent of cases of infectious syphilis treated by private physicians are 
being reported, and that while only 20,000 cases of infectious syphilis were 
reported by clinics and physicians, probably closer to 100,000 were diag- 
nosed and treated in fiscal 1962. 

The potential loss to the control program arising from the omission 
of contact investigation of infectious syphilis cases — which is more difficult 
for cases handled by private physicians than those in public clinics — is 
shown by Figure 25 from an article by Moore. ^ 



NEXT STEPS 



It is completely clear today, as some have been saying for years, that 
the private physician will have to be brought into the control program 
before syphilis can be controlled. Studies have shown that private physi- 
cians can be educa«ted to report cases of syphilis and to cooperate with 
having contact investigation carried out on their cases of infectious syphiUs. 



Syphilis Through the Ages 611 

This teaming up of the private physician and the health department in 
the field of venereal disease control may lead the way to closer cooperation 
in other fields and this partnership might become as important as venereal 
disease control itself. 

Also, the fact that social forces decreased the attack rate of syphilis 
before effective treatment and control efforts became possible should make 
us realize that social factors can change and that possibly some of the 
recent increase may be due to social factors. We know that change in 
treatment methods and the economic status of the population has made 
the private physician more important than the clinic and we also know 
that even factors in the epidemiology of syphilis may change. Recent 
evidence points to the greater importance of homosexual practices in the 
spread of syphilis today. Also, syphilis has always been acquired mostly by 
the young, and perhaps the teen-ager may be becoming an even more 
important factor. Intensive research of this disease and the conditions 
under which it is transmitted obviously must continue, and even be 
intensified in order to insure our ability to control it. 



REFERENCES 

1. (a) Pusey, W. A.: The History and Epidemiology of Syphilis. Springfield, 111., 

C. C Thomas, 1933. 
(6) Ibid., p. 21. 
(c) Ibid., p. 8. 

2. Hunter, J.: A Treatise on the Venereal Disease, with notes by P. Ricord and 

F. J. Bumstead. Philadelphia, Blanchard & Lea, 1853. 

3. (a) Ricord, P.: Venereal Diseases (Revision of translation by Drummond). New 

York, Gordon, 1942. 
(6) Ricord, P.: Venereal and Other Diseases (Translated by V. De Meric). Phila- 
delphia, Barrington & Haswell, 1849. 

4. (a) Fournier, A.: Syphilis and Marriage (Translated by P. A. Morrow). New York, 

Appleton, 1881 . 
(6) Ibid., p. 22. 

(c) Ibid., p. 113. 

(d) Ibid., p. 20. 

5. (a) Buret, F.: Syphilis in Ancient and Prehistoric Times, Vol. I (Translated by 

A. H. Ohmann-Dumesnil). Philadelphia, F. A. Davis Co., 1891. 
(6) Buret, F. : Syphilis in the Middle Ages and in Modern Times, Vol. II (Translated 

by A. H. Ohmann-Dumesnil). Philadelphia, F. A. Davis Co., 1895. 
(c) Buret, F.: Vol. I, p. 156. 

6. (a) Garrison, F. H.: History of Medicine. Philadelphia, W. B. Saunders Co., 1929, 

p. 189. 
(6) Ibid., p. 416. 

7. Hazen, H. H.: Syphilis. St. Louis, C. V. Mosby Co., 1919, p. 23. 

8. Moore, J. E.: An evaluation of public health measures for the control of syphilis. 

Am. J. Syph., Gonor. & Ven. Dis. 35: 101, 1951. 

9. Hinrichsen, J.: Venereal disease in the major armies and navies of the world, (a) Am. 

J. Syph., Gonor. & Ven. Dis. 28: 736, 1944; (6) Ibid., 29: 80, 1945; (c) Ibid., 29: 
229, 1945. 
10. Vonderlehr, R. A. and Usilton, L. J.: The chance of acquiring syphilis and the 
frequency of its disastrous outcome. Ven. Dis. Information 19: 396, 1938. 



612 William L. Fleming 

11. VD Fact Sheet, 1961 (18th revision). Public Health Service Publication No. 341, 

U. S. Department of Health, Education and Welfare, 1962. 

12. Parran, T. and Vonderlehr, R. A.: Plain Words about Venereal Disease. New York, 

Reynal & Hitchcock, 1943. 

13. National Study of Venereal Disease Incidence. Unpublished data from American 

Social Health Association. 

University of North Carolina School of Medicine 
Chapel Hill, North Carolina 



The Oslo Study of the Natural Course 
of Untreated Syphilis 

An Epidemiologic Investigation Based on a Re-study 
of the Boeck-Bruiisgaard Material 



E. GURNEY CLARK, M.D., Dr.P.H.* 
NIELS DANBOLT, M.D.** 



Nowhere in the world was there a more unique opportunity to 
learn what happens when early syphilis goes untreated than from the 
files of Professor Boeck of Oslo, Norway. His deep scientific conviction as 
to the inadequacies of the specific treatment of his time led him to 
withhold treatment from 1978 patients with primary and secondary syph- 
ilis during the 20-year period 1891-1910. Community protection from 
infection was aided by the hospitalization of these patients until all traces 
of the disease had disappeared (from 1 to 12 months, average 3.6 months). 
In 1929, his successor, E. Bruusgaard,^ reported on a follow-up study of 
473 of these patients and provided information on the outcome of untreated 
syphilis, which formed the basis for prognostic statements on syphilis for 
more than 25 years. From 1948 to 1951, in the department of Bruusgaard's 
successor, Professor Niels Danbolt, Trygve Gjestland carefully planned 
and executed an epidemiologic re-study of this unique clinical material in 
its entirety.^ The study method and the results should be of interest to all 
physicians and public health workers. 

The objectives of this paper are: (a) to review and appraise this 
important contribution to the syphilologic literature; (b) to present some 
of the details of the planning and execution of the investigation; (c) to 
provide a brief resume of the results of the study for the American literature 
and (d) to emphasize the significance of this investigation for the natural 
course of chronic disease. 



* Professor of Epidemiology, College of Physicians and Surgeons, New York, N. Y. 
** Professor of Dermatology and Syphilology, University of Oslo, Norway 

613 



614 E. GuRNEY Clark, Niels Danbolt 

The initial phase of this study began in 1948 with the original sugges- 
tions of Drs. J. E. Moore, N. Danbolt, T. Guthe and others. These sug- 
gestions were incorporated by Gjestland into a plan which included: 
(1) definition of the nature, extent and significance of this problem, a 
clarification of the objectives and a proposal of important questions which 
might be answered by a re-study of this material ; (2) appraisal of existing 
information; (3) formulation of hypotheses; (4) testing of hypotheses and 
(5) conclusions and practical application. 

The nature of the overall problem was quoted from Stokes:^ ''No one 
who has had even a limited experience in answering the questions on which 
students and physicians seek information in their practical contacts with 
the disease can fail to realize that the great ailment of modern syphilological 
practice is a lack of comprehension of the why and wherefore, rather than 
the what to do." Comprehension of the ''why and wherefore" lay in a 
better understanding of the prognosis of untreated syphilis. The beneficial 
effects of treatment in modifying the biologic course of syphilitic infection is 
well known. What was lacking was quantitative information on what 
happens to those who go untreated. The reason for this lack lay in the 
absence of studies of large groups of untreated patients, thoroughly 
diagnosed and observed over sufficient periods of time. 

Further significance of the problem of prognosis is emphasized by the 
reliance of modern syphilologists upon the results of Bruusgaard's investi- 
gation of only 473 of Boeck's 1978 patients in 1925-1927. 

Of prime importance in determining the potential contribution of this 
investigation were the examination of the diagnostic criteria of those times 
and an analysis of the validity of the diagnoses made in Boeck's department. 
These diagnoses were based entirely on clinical examination and subse- 
quent observation (because neither darkfield nor serologic tests for syphilis 
were employed before 1910). A large sample of the hospital records were 
examined carefully by the authors of this review and in their opinions 
there is no doubt that a great majority of these patients had early syphilis. 

The objectives of the Oslo study were stated as follows: "(1) To trace 
as many patients as possible to an 'end point,' defined as the last observa- 
tion, living or dead; (2) to collect the maximum amount of clinical data 
(including data on treatment) on each patient from the date of his original 
discharge from Boeck's department through the interim period and up to 
the 'end point'; (3) to determine the causes of death through a study of 
post-mortem examinations, hospitalizations, death certificates, etc., with 
the maximum amount of accuracy, and (4) to examine at the Rikshos- 
pitalet as many living patients as possible and to employ as complete 
examinations for syphilis as circumstances will permit and to have examined 
elsewhere according to the same principles those patients who, for some 
reason or other, could not be brought to the Rikshospitalet."^ 

The questions asked from the beginning were: What is the final out- 



The Oslo Study of the Natural Course of Untreated Syphilis 615 

come in terms of late syphilis, duration of life and causes of death in per- 
sons who are untreated for symptomatic early syphilis? 

The appraisals of existing information were limited to : (a) classification 
and critical evaluation of other investigations on the outcome of untreated 
syphilis and (h) well known authoritative reports dealing with the various 
aspects of syphilitic infection: secondary relapse, benign late syphilis, 
cardiovascular syphilis, neurosyphilis, etc. Gjestland's evaluations of the 
literature on these specific aspects of syphilitic infection in relation to his 
own data are among the worthwhile contributions of this investigation, 
particularly the presentation and evaluation of the essential items to 
consider when comparisons between studies are attempted. 

Following an appraisal of the most pertinent literature, a careful study 
of the Boeck records and a detailed and critical appraisal of Bruusgaard's 
results, the next step was to consider the specific questions for which the 
Boeck data might provide answers. Thus, among patients untreated for 
primary and secondary syphilis and with no, some, or unknown subsequent 
treatment: (1) What are the frequencies of secondary relapse, of benign 
late syphilis, of late symptomatic syphilis, of life-long latency and of 
spontaneous cure? (2) What are the effects on longevity, on causes of 
death and on mortality over that of nonsyphilitics? (3) Does age at time 
of infection influence outcome? (4) Does sex influence outcome? (5) Is 
morbidity from conditions other than syphilis greater than among non- 
syphilitics? 

On the basis of these questions and on the appraisal of pertinent 
literature, the study was designed to provide support or denial of the 
following hypotheses: (1) Syphilis, untreated in its primary and secondary 
stages, has a favorable outcome in a majority of instances. (2) Serious 
results are more frequent in males than in females. (3) Untreated syphilis 
prolongs the period of community danger of infection. (4) There is no way 
to predict the outcome in individual cases. (5) Syphilitics have a higher 
morbidity and mortality from other conditions than do nonsyphilitics. 



DESIGN OF INVESTIGATION 

The study group finally decided upon comprised 1404 individuals 
drawn from Boeck's original series of 1978 hospitalized patients. The ones 
eliminated were 574 Norwegian nonresidents of Oslo and non-Norwegians. 
It was believed that limiting the tracing to Norwegian residents of Oslo 
would not bias the overall study and at the same time would simplify 
tracing and aid in the selection of controls. 

The 1404 Norwegian residents of Oslo came from the underprivileged 
section of society which at that time lived in the east zone of the city. 
There were 958 females and 446 males. Between the ages of 0-14, there 
were 41 females (4.2 per cent) and 32 males (7.2 per cent); ages of 15-24, 



616 E. GuRNEY Clark, Niels Danbolt 

591 females (61.7 per cent) and 208 males (46.7 per cent); ages of 25-39, 
268 females (28.0 per cent) and 171 males (38.3 per cent) and in the J^O and 
over group, 58 females (6.1 per cent) and 35 males (7.8 per cent). 

Among both males and females the highest proportions were among 
the 15-24 age groups and the next highest among those 25-39 years of age. 

The **Search Order" 

The complete plan of investigation cannot be given in detail here, but 
the thoroughness with which this plan was considered and undertaken and 
the method of search and identification is an outstanding example of 
careful planning. Two essential preliminary requirements for retrospective 
studies of this kind are the establishment of a ''search order" and a system 
of identification of names and recorded data. A ''search order" is a listing 
of possible sources of information in pre-arranged order which will assure 
a minimum of duplication of effort and, if followed routinely, will add a 
considerable degree of accuracy to the identifying process. Every name 
should be seached through the entire list even when it appears to have 
been located in the first source searched. Similarities of name and other 
identifying data make this necessary. Identity can be established objec- 
tively only by comparing a number of personal, geographic and clinical 
characteristics each time new information is found. 

Chief Sources of Information and Order of Search. The following is a 
list of the sources of identifying and clinical information, arranged in the 
order in which they were searched. This is the "Search Order" through 
which each name was taken. 

1. Death registers 

2. The Department of Dermatology and Venerology of the Rikshospitalet 

3. The Oslo Bureau of Indigents 

4. Bureaus of Indigents elsewhere* 

5. The Central Bureau of Statistics' Marriage Registry for Oslo (women only) 

6. The Oslo Population Register 

7. The Oslo City Health Department, Venereal Disease Division 

8. The Municipal Hospital of Oslo, Venereal Disease Division 

9. Parish minister, sheriff or local Population Register at patient's place of birth* 

10. Parish minister, sheriff or local Population Register at patient's place of resi- 
dence prior to his settling in the City of Oslo* 

11. Individual sources, especially relatives of the patient, but also many others not 
specified* 

12. The Oslo City Health Department and the Central Bureau of Statistics (for 
transcription of death certificates) 

13. Mental hospitals, psychiatric wards, neurological and other hospital wards 
(private practitioners as indicated) 

Collection of Data 

From time to time the operation required and received the cooperation 
of various hospital staffs and many persons employed in the official record 
bureaus of the country. Every bit of information found on every patient 
was checked according to the identification plan and all records (hospital 

* These are supplemental sources. 



The Oslo Study of the Natural Course of Untreated Syphilis 617 

and others) were recorded in toto in the master record folder. The record 
system, organized before the tracing began, comprised: (a) an index card 
file which served as a key to the other files and an index of the current 
status of tracing on each patient; (5) a master folder which contained the 
transcribed records from hospitals, admitting agencies and physicians' 
offices and (c) a summary record devised to permit analysis of the material 
as efficiently as possible in terms of the proposed questions and to give 
information on the natural course of syphilis infection. 

At the close of the investigation in August, 1951, some usable infor- 
mation had been obtained on 81.7 per cent of the 1,404 study group. In 
Table 1 are the results of the tracing efforts. The ''known" group comprises 
those on whom a diagnosis could be established at a classifiable ''end point." 
They were alive and examined during the investigation period, or if dead, 
the time and status at death could be determined. "Partially known" 
refers to those with one or more observations during the years following 
discharge from Boeck's department, but not to the same clear-cut "end 
points" of diagnosis as those of the "knowns." "Unknown" means no 
information following discharge from Boeck's department. For 83.9 per 
cent of the males and for 80.7 per cent of the females there was some 
significant information. Still alive in 1951 were 16.1 per cent of males and 
19.5 of females. This is a high and probably unique degree of success in 
tracing a population group some 40 to 60 years after the original event. 

On the 953 persons classed as "known" there were 3584 recorded 
observations (an average of 3.8 per person), and on the 194 "partially 
known," 523 observations (2.7 per person), the overall average being 3.6 
observations. Of the "knowns," 259 were still alive (Table 1) and of these, 
83.4 per cent were examined in Norway or elsewhere during or shortly 
prior to the period of investigation (1949-1951). For the remaining 16.4 
per cent (43 persons), information was obtained directly or indirectly as to 
their health status. Information on the dead (694 persons) came from 
physical examinations immediately prior to death in approximately 29 per 

Table 1. Oslo Study of Untreated Syphilis: Tracing Status {^'^Known,^^ 
''Partially Known;' and ''Unknown'') 7951, by Sex 

male female total 

tracing status 

No. Per cent No. Per cent No. Per cent 



'Known" 

Living 72 16.1 187 19.5 259 18.4 

Dead 259 58.1 435 45.4 694 49.4 



Subtotal 331 74.2 622 64.9 953 67.9 

"Partially known" 43 9.6 151 15.8 194 13.8 



Subtotal 

''Unknown" 


374 

72 


83.9 
16.1 


773 
185 


80.7 
19.3 


1147 
257 


81.7 
18.3 


Total 


446 


100.0 


958 


100.0 


1404 


100.0 



618 E. GuRNEY Clark, Niels Danbolt 

cent, from autopsy examinations in 30 per cent, from physical examinations 
a short time prior to death in 15 per cent and from death certificates or 
other sources in 26 per cent. 



RESULTS 

For conclusions and practical applications, the collected and analyzed 
data are presented to show the extent to which the questions have been 
answered and the hypotheses verified for practical use. The results are 
given and discussed under the following chapter headings in Gjestland's 
monograph :2 Clinical Secondary Relapse; ''Benign" Late Syphilis; Cardio- 
vascular Syphilis; Neurosyphilis; Other Late Syphilis; Mortality; and 
Spontaneous Cure. Only brief and incomplete presentations of these results 
can be made in this paper. 

Type of Lesion 

Clinical Secondary Relapse. This is one of the most significant of the 
analytical sections, contributing much to knowledge of the natural course 
of syphilis; so much, in fact, that the entire concept of relapse may be 
modified as a result of these findings. Although the opinion is not universal, 
much of the modern literature states that clinical secondary relapse is a 
phenomenon related only to inadequate treatment of early syphilis or must 
be regarded as progression. The Oslo study shows conclusively that clinical 
secondary relapse occurs in the absence of treatment. 

Among the 244 patients (23.6 per cent) who developed relapse, 46 
(18.9 per cent) experienced two; 8 (3.3 per cent), three and 1 (0.4 per cent), 
four outbreaks; i.e., multiple outbreaks occurred in 22.5 per cent. Further- 
more, both from the clinical and public health standpoints it is important 
to note that in 85 per cent of instances the relapsing lesions involved the 
mouth, throat or anogenital regions. 

More than two-thirds of the relapsers had relapsed by the end of six 
months (males 72.3 per cent, females 65.1 per cent); by the end of a year, 
92.3 per cent and 86.6 per cent; at two years, 96.9 per cent and 93.3 per 
cent and by the end of five years, 100 per cent. 

Benign late syphilis occurred in 14.4 per cent of males and 16.7 per 
cent of females. This is in general thought to be related to an upset in the 
parasite-host relationship resulting from reactivation of remaining trepo- 
nemes in a sensitized host. 

In males this was higher in the 0-14 and 40 and over infected age 
groups and in females higher in the 15-39 age group. Of those observed 
with benign late syphilis, 25 per cent of the males and 34.7 per cent of the 
females had from two to seven episodes of this manifestation, showing 
again a rhythmic feature of this disease. Solitary (single structure) lesions 
were more common (90 per cent) than multiple structure involvement; 



The Oslo Study of the Natural Course of Untreated Syphilis 619 

70 per cent were skin, 9.6 per cent skeletal and 10.3 per cent mucous 
membrane lesions. In the remaining 10 per cent, which were multiple 
structure lesions, the skin was one of the structures involved in more than 
half of the instances. Lesions developed from the first to the forty-sixth 
year after the healing of secondaries, the majority developing by the end 
of the fifteenth year. When the probabilities were calculated, males and 
females showed significant differences at 15, 30 and 35 years, females being 
higher in each instance. 

Cardiovascular Syphilis. Of particular interest is the fact that none 
of those infected before the age of 15 were found to have this type of late 
syphilis and, as expected in each age group, the proportions of males were 
significantly higher than those of females, the total rates for males being 
almost twice that for females, 13.6 per cent and 7.6 per cent, respectively. 

Neurosyphilis. Of the 62 persons in the group under study who 
developed neurosyphilis, 31 (9.4 per cent) were males and 31 (5.0 per cent) 
females. The lesions were divided as follows: diffuse meningovascular 
syphilis (males 3.6 per cent; females 1.7 per cent); general paresis (males 
3.0 per cent; females 1.7 per cent); tabes dorsalis (males 2.5 per cent; 
females 1.4 per cent) and gumma of the brain (males 0.3 per cent; females 
0.2 per cent). It is of interest here to note that neurosyphilis did develop 
among those infected under the age of 15. Of this age group, 6.1 per cent 
developed neurosyphilis, with a male-female ratio of approximately 4 to 1. 
None of the 28 males over 40 at infection developed neurosyphilis, whereas 
two of 45 females did. 

Of the 62 persons with neurosyphilis, 18 were alive and examined 
during the period of the investigation, these being equally divided among 
males and females. Of the dead, neurosyphilis was recorded as the primary 
cause of death in two-thirds of the instances. In the other third, neuro- 
syphilis was present but unrelated to the cause of death. 

Other Late Syphilis. Among 953 patients classified as ''known," only 
two were found to have other types of late syphilis. Two females had 
gummas of the liver, one found at autopsy and one diagnosed clinically. In 
each instance the manifestation was considered to be the primary cause of 
death. 

Mortality 

The mortality of this series of patients was studied by Gjestland from 
three viewpoints: (a) the actual causes of death; (6) the probabilities of 
dying primarily as a result of syphilis infection, and (c) the excess mortality 
of syphilitics as compared with a control series. 

Table 2 shows the primary causes of death among the 694 known 
dead. Syphilis was the primary cause of death in 15.1 per cent of the males 
and 8.3 per cent of the females, a ratio of 1.8 to 1. Among males, syphilis 
ranked second and among females, fifth as a cause of death. In each group, 
tuberculosis led the causes of death and in females more died of cancer 



620 E. GuKNEY Clark, Niels Danbolt 

Table 2. The Oslo Study of Untreated Syphilis: Primary Causes of Death 
by Sex Among 694 Known Dead 



MALES 



PRIMARY CAUSES OF DEATH 



No. Percent Rank No. Percent Rank 



Tuberculosis 45 17.4 1st 74 17.0 1st 

Syphilis 39 15 . 1 2nd 36 8.3 5th 

Cancer and other tumors 32 12.4 3rd 71 16.3 3rd 

Diseases of circulatory system 28 10.8 4th 72 16.6 2nd 

Diseases of respiratory system 25 9.7 5th 42 9.7 4th 

Sudden— unknown, unspecified 20 7.7 6th 18 4.1 8th 

Diseases of urinary and genital tract 16 6.2 7th 16 3.7 9th 

Diseases of ner,vous system and 

sense organs^ 14 5.4 8th 34 7.8 6th 

Accidental deaths 11 4.2 9th 9 2.1 10th 

Diseases of digestive system 7 2.7 10th 24 5.5 7th 

All others 22 8.7 39 8.9 



and diseases of the circulatory and respiratory system than of syphilis. 
Thus, among a 100 per cent syphilitic population, 84.9 per cent of males 
and 91.7 per cent of females died of other causes. 

The cumulative probability of dying directly as a result of syphilis 
was 17.1 per hundred in males and eight per hundred in females by the 
end of 40 years of infection among this group of patients. 

In order to study possible cause-and-effect relationships for the excess 
mortality of syphilitics over nonsyphilitics, a control group was chosen 
from the population of the City of Oslo for comparison with the mortality 
experience of Boeck's patients. It was found that most of his patients came 
from the eastern parishes of the city and their mortality experience could 
be compared by age, sex and cause and by decade with the population 
from which they came. This was studied in considerable detail and will be 
reported in detail in a separate publication.^ Certain of these findings are 
touched upon in Table 3 and the following paragraph. 

Table 3 shows that these untreated syphilitics had an excess in mor- 
tality over that expected of 53 per cent in males and 63 per cent in females 
(all ages), and there was some degree of excess in every age group except 
males 10-19. The excess was most pronounced in males 40-49 and in 
females 30-39. A similar picture of excess mortality was found when the 
mortality experiences of the eastern and western parishes were compared 
according to age, sex and decade; the eastern group with lower economic 
status showed excess mortality over that of the west in practically every 
category of comparison. The average excess mortality of the east over the 
west (all ages) was 16 to 27 per cent among males and 25 to 38 per cent 
among females. 



The Oslo Study of the Natural Course of Untreated Syphilis 

Table 3. The Oslo Study of Untreated Syphilis: Mortality Excess in 

Syphilitics as Compared to That Expected on Basis oj Experience of 

Residents of Eastern Parishes of Oslo by Age and Sex from 

189Chig40 



621 







MALES 






females 




AGE 


Expected 


Observed 


Excess 
Per cent 


Expected 


Observed 


Excess 
Per cent 


10-19 


2.3 


1 





4.4 


5 


14 


20-29 


13.7 


15 





29.4 


42 


43 


30-39 


21.5 


33 


53 


43.1 


84 


95 


40-49 


24.8 


55 


122 


36.8 


69 


88 


50-59 


30.5 


48 


57 


38.3 


60 


57 


60-69 


28.4 


41 


44 


26.6 


41 


54 


70 and over 


18.9 


21 


11 


25.3 


31 


23 


All ages 


140.1 


214 


53 


203.9 


332 


63 



Spontaneous Cure 

There are many statements in the literature about the frequency of 
spontaneous cure, but very little evidence is available to support the 
estimates. One of the barriers to an understanding of this problem is the 
strictness of definitions of spontaneous cure made by various authors. 
These definitions of spontaneous cure are too rigid to permit quantitative 
evaluation. More practical is a consideration of the extent of disability 
during the lifetime of the persons involved. It was estimated that between 
60 and 70 out of every 100 of these patients went through life with a 
minumum of inconvenience despite no treatment for early syphilis. This 
gives no encouragement to withhold treatment because the final outcome 
in any individual cannot be predicted and, too, syphilis is still a transmis- 
sible disease when untreated and can cause serious difficulties among 30 
to 40 out of each 100 who remain untreated. 



SUMMARY 



This re-study represents a striking example of the application of the 
modern epidemiologic approach. In addition to the scientific contribution 
of this investigation, an outstanding illustration of international scientific 
cooperation has been demonstrated. 

The remarkable degree of success in obtaining significant information 
on approximately 80 per cent of the study group, 1404 Norwegian residents 
of Oslo of 1891-1910, was undoubtedly due to the careful planning which 
preceded the tracing efforts. This planning included : (a) a consideration of 
the nature, extent and significance of the problems of untreated syphilis; 



622 E. GuRNEY Clark, Niels Danbolt 

(6) an appraisal of existing information on the subject; (c) the setting up 
of hypotheses to be tested and questions to be answered and (d) a detailed 
outline for a practical experiment design. The pretracing experiment 
design comprised: the selection of the study group; the listing of possible 
sources of information; a plan for orderly tracing; a provision for the 
collection and recording of information; plans for ''controls" and an 
outline for the analysis of data. 

The study was undertaken with the ultimate objective of providing 
information on the natural course of syphilis according to as many indices 
as the material would allow. 

One of the very significant contributions of this investigation is the 
information obtained on clinical secondary relapse: 23.6 per cent of these 
patients experienced this manifestation within five years of discharge from 
the hospital (males 22.7 per cent; females 24.0 per cent) and of these 
approximately one-fourth had multiple episodes. 

Benign late syphilis occurred in 14.4 per cent of males and 16.7 per 
cent of females. It was observed as early as the first year after discharge 
and as late as the forty-sixth year, the majority developing by the fifteenth 
year. There was some evidence of earlier appearance in females than in 
males and some suggestion that the probability of development is greater 
among females. 

Cardiovascular syphilis was observed to have developed in 13.6 per 
cent of males and 7.6 per cent of females, no cases occurring in those 
infected before the age of 15. 

Neurosyphilis did develop in patients who were infected before the 
age of 15, but not in males infected after the age of 40. In neurosyphilis 
there was a two to one ratio of males to females (males 9.4 per cent and 
females 5.0 per cent). 

The mortality from syphilis among males was twice that of females, 
but in neither sex was it an important cause of death. It was second as a 
cause of death in males and fifth in females, but approximately 90 per cent 
of deaths were from other causes. There was a definite excess mortality 
among these syphilitics as compared to the population group from which 
they came. 

No evidence was found to support the idea that either clinical sec- 
ondary relapse or benign late syphilis has prognostic importance. 

This is probably the most comprehensive study of untreated syphilis 
that has yet been made, and the great mass of data that have been collected 
will provide the basis for additional contributions to our knowledge of 
syphilitic infection. This brief review cannot do justice to this monumental 
piece of work comprising a monograph of some 500 pages,^ with 83 tables 
and 12 figures and an annex of 70 pages with 30 tables and two figures. 
Gjestland's contribution, providing the medical literature the long awaited 
re-study of the Boeck-Bruusgaard material, will stand as a model of care- 
fully planned and successfully executed field research. 



The Oslo Study of the Natural Course of Untreated Syphilis 623 

REFERENCES 

1. Bruusgaard, E. : tjber das Schicksal der nicht spezifisch behandelten Luetiker. Arch. f. 

Dermat. u. Syph. 157: 309, 1929. 

2. Gjestland, T. : The Oslo Study of Untreated Syphilis — An epidemiologic investigation 

of the natural course of untreated syphilis based on a restudy of the Boeck- 
Bruusgaard material. Submitted to Acta Derma to- Venereologica, for publication 
as a Supplement in 1955. 

3. Stokes, J. H., Beerman, H. and Ingraham, N. H., Jr.: Modern Clinical Syphilology. 

3rd Ed. Philadelphia, W. B. Saunders Co., 1944. 

4. Gjestland, T., Heen, R. and Trier, G.: A Regional Investigation of the Mortality in 

the City of Oslo during the Period 1890-1940 (to be printed). 

600 West 168th Street 

New York 32, N. Y. (Dr. Clark) 



Infectious Syphilis 



HARRY PARISER, M.D., D.Sc. (Med.)* 



INTRODUCTION 

The organism of syphilis, Treponema pallidum, is an anaerobe requiring 
moisture and tissue for survival. It is able to grow and survive despite body 
defense, but dies quickly away from tissue and moisture. Because of its 
inability to survive on fomites, we can to a large extent discount as not 
authenticated most of the reported cases of transmission by indirect means 
(door knobs, dishes, toilet seats, etc.). The physiologic secretions (vaginal, 
salivary and seminal fluid) collected in all stages of the disease, both early 
and late, have been shown in controlled experiments to be noninfectious. 
The blood, however, may contain the organism in abundance in the early 
years of infection and at irregular intervals in the later years. From this 
source the organism may be discharged into the fetal circulation during 
the early stages of pregnancy or into the vaginal tract by way of the 
menstrual blood. The organism does not survive in the vaginal tract after 
menses are completed unless lesions are present from which the organism 
is repeatedly discharged. 

Transmission of syphilis reduced to its simplest terms is a lesion-to- 
lesion affair except by means of the blood. Unfortunately, the transmitting 
lesion is often painless, inconspicuous or hidden. 



CLASSIFICATION 

The untreated disease passes through the following stages: 

1. The incubation period of three weeks' duration with limits of 10 to 
60 days. During this stage there are no signs or symptoms of 
infection. 



Read at, Syphilis: A Symposium, Vanderbilt University School of Medicine, Nashville, 

Tennessee, May 17-18, 1963. 
* Director, Venereal Disease Control Program, Norfolk, Virginia 

625 



626 Harry Pariser 

2. The primary stage (chancre) of one to five weeks' duration. This 
consists of the appearance of a lesion at the site of inoculation. 

3. The secondary stage appearing two to ten weeks later. This is 
usually manifested by a generalized eruption lasting about two to 
six weeks. 

4. The latent or quiescent stage lasting two to 20 or more years. This 
is a stage in which there are no clinical signs or symptoms; the 
diagnosis is based on the presence of reactive serologic tests and 
negative spinal fluid examination. Latency is divided into two 
phases — early, within the first two years of infection, and late, of 
more than two years' duration. Some prefer to use four years as 
the dividing line between early and late latency. 

5. Late or symptomatic stages (cardiovascular, central nervous sys- 
tem, etc.). 

Infectious syphilis includes the primary, secondary and early latent 
stages. During the stage of early latency there are in the untreated patient 
periodic relapses to the secondary types of lesions followed by spontaneous 
healing. This relapsing tendency occurs for the most part during the first 
two years of infection. Thereafter, in 95 per cent of cases, immunologic 
changes occur which prevent the appearance of infectious skin lesions but 
not progression of the organism in other body tissues. Stated in other terms, 
the stages of primary and secondary syphilis are to be regarded as contin- 
uously infectious, and of early latent syphilis intermittently so, depending 
upon relapse. In the individual case there is no positive end point of 
transmissibility since relapse has been reported to occur as long as 20 
years after the original infection, and in my own experience was seen up 
to 13 years after the infection was acquired. On the other hand, some 
patients probably become noninfectious as early as six months after the I 
disease was contracted. 

The true incidence of relapse in untreated syphilis is unknown. My 
experience indicates that much of this relapse may be subclinical or unob- 
trusive, often consists of only a few lesions, and is of greater frequency 
than generally suspected. 

It would be misleading to assume that the stages of infectious syphilis 
represent isolated phenomena from the primary through the early latent 
stages. Rather we should regard these stages as merely representative of 
different manifestations of the continuous battle between the organism and 
the body. Latency is merely a convenient clinical description of the stage 
in which no outward manifestations of this continuing and active struggle 
are apparent. 

Two factors determine the status of infectiousness: (1) the duration 
of the disease as previously discussed, and (2) treatment with penicillin or 
other treponemicidal antibiotics which render open lesions spirochete-free 
within 24 hours. 



Infectious Syphilis 



627 



CLINICAL MANIFESTATIONS 



Primary Syphilis 

The typical lesion has an eroded surface with serous discharge, is 
painless, and of raw-ham color (Fig. 1). The primary lesion, however, may 
vary in appearance from a small erosion (Fig. 2) to a deep ulcer (Fig. 3). 
At times the lesion is not even eroded but appears as an area of induration 
(Fig. 4). The lesion is usually but not invariably single, and is accompanied 
by painless, nonsuppurative, rubbery, satellite adenopathy. The ''typical" 
classically described lesion probably occurs less frequently than the ''atyp- 




Fig. 1 Fig. 2 

Figure 1. A typical appearing primary lesion indurated and erosive with serous 
discharge. 

Figure 2. A pin head sized questionably indurated primary lesion of the frenulum. 




Fig. 3 Fig. 4 

Figure 3. A deep, painful, ulcerative primary lesion of the anterior thigh. 
Figure 4. An indurated nonerosive area of the shaft of the penis. Treponema 
pallidum found after the surface was abraded. 



628 



Harry Pariser 




Fig. 5 Fig. 6 

Figure 5. A perianal primary lesion. Patient refused to allow vaginal coitus for 

fear of pregnancy. 

Figure 6. A primary lesion of the tongue in a homosexual who admitted genito- 

buccal contact. 




'^ 




Fig. 7 Fig. 8 

Figure 7. A typical symmetrical slightly indurated papular secondary. 
Figure 8. Hyperpigmented annular lesions with raised depigmented border of 

the face. This type of eruption is confined almost exclusively to the Negro and is almost 

pathognomonic of secondary syphilis. 



Infectious Syphilis 629 

ical" variants. The chancre may be present in an area in which the accom- 
panying adenopathy is inaccessible, such as the perianal region (Fig. 5) or 
on the cervix where the patient is unaware of its presence. Extragenital 
primary lesions particularly of the fingers and hps tend to be somewhat 
painful. 

It has been my experience that the physician's index of suspicion 
drops sharply when the primary lesion is present in an area other than the 
penis or vulva, and more likely than not, syphilis will not be considered in 
the diagnosis when the lesion is situated away from the genital region 
(Fig. 6). 

Secondary Syphilis 

The secondary eruption may also vary greatly in appearance, and 
may be conspicuous or inconspicuous. Morphologically the eruption may 
be macular, papular, papulosquamous, grouped follicular, rarely pustular 
or nodular, and almost never vesicular. In the oral cavity the lesions are 
usually eroded and around the genitalia may become vegetative (condylo- 
ma tous). The typical eruption is symmetrical (Figs. 7 and 8), the atypical 
and relapsing eruptions often may not be. Usually involved are the oral 
cavity (Fig. 9), the anogenital area (Fig. 10), and the palms and soles 
(Fig. 11). The lesions are often slightly indurated and not pruritic. In 
relapsing secondary syphilis, the lesions tend to be arciform or annular 
(Figs. 12 and 13). 

Secondary lesions covered with a protective epithelial coat on the 
glabrous skin are not infectious, but become eroded around the anogenital 
area due to constant moisture. The disease thus becomes primarily venereal 
from a biologic point of view and not from any malevolent design for 
punishment. Secondary syphilis is the most highly contagious stage since 
there are many lesions from which the infection may spread rather than 
the usual single lesion of primary syphilis. Accompanying generalized 
adenopathy is a very important sign. Occasionally iritis, patchy alopecia, 
and sore throat are present. Some patients have slight constitutional 
symptoms, such as fever or malaise, but usually these are so mild that they 
are for the most part ignored. 

Early Latent Syphilis 

Early latent syphilis may be presumed to exist if a history can be 
obtained of probable primary or secondary lesions within the previous two 
to four years, or of nonreactive tests within the same time followed by 
reactive tests. The presence of a standard high-titered quantitative reading 
(1:16 dils or over) repeated and confirmed as syphilitic by a treponemal 
test in individuals 25 years of age or less, is also presumptive evidence of 
probable early latent syphilis if congenital syphilis can reasonably well be 
ruled out. 



630 



Harry Pariser 




Fig. 9 Fig. 10 

Figure 9. Erosive secondary lesions under the tongue (mucous patches). 
Figure 10. Condylomata of the anogenital area. 




Figure 11. Papular lesions of the palms. 




Fig. 12 Fig. 13 

Figure 12. Arciform relapsing secondary lesions of the forearm. 
Figure 13. Arciform relapsing secondary lesion of the chin. 



PLATE I 




Fig. 14. Patient unaware of lesions: 
Two syphilitic papules of the buttock. 



Fig. 15. Patient unaware of the lesion. 
A single syphilitic erosive follicular lesion 
of the posterior scrotum. 




Fig. 16. Patient unaware of lesion, 
Syphilitic erosive lesion within nostril. 



Fig. 17. Patient unaware of lesions. 
Three erythematous syphilitic papules of 
the forearm. 



Infectious Syphilis 631 

LABORATORY TESTS 

Darkfield Examination 

Properly prepared darkfield examination will reveal the organism in 
most primary and secondary syphilitic lesions, but the organism may be 
difficult to find in involuting lesions, in lesions with considerable detritus, 
or in which topical antiseptics or caustics have been applied. Such unclean 
or locally treated lesions if soaked periodically in saline for a day or two 
will, if syphilitic, show organisms. It is best to read the darkfield immedi- 
ately but this reading may be delayed if the serum is sealed in special 
capillary tubes to keep the specimen from drying. Experience is necessary 
for correct morphologic identification of the organism because other genital 
spirochetes may resemble those of syphilis. In the mouth, saprophytes are 
present which so closely resemble Treponema pallidum that darkfield 
examination of specimens taken from the oral cavity is usually unreliable. 
At the present time the fluorescent darkfield technique is being evaluated 
with some initial success on specimens taken from presumably infectious 
lesions. The usefulness of the darkfield procedure may thus be extended 
since this method permits drying of the specimen and therefore delayed 
reading, as well as differentiation between Treponema pallidum and sap- 
rophytic morphologically similar organisms. Organisms may be identified 
in lesions of the glabrous skin by scraping them, or by puncturing sateUite 
lymph nodes, and then examining the serous exudate by the darkfield 
technique. A positive darkfield permits an absolute immediate diagnosis of 
the disease. 

It is important to remember that the appearance of primary and sec- 
ondary syphilitic lesions may be modified by small amounts of antibiotic given 
in inadequate doses for diseases other than syphilis, and if recently given, 
may eliminate the organism from a lesion that would otherwise show it. 

Serologic Tests 

The standard serologic tests for syphilis become reactive about one to 
two weeks after the appearance of the primary lesion or four to five weeks 
after infection is acquired. Quantitative titers rise rapidly thereafter. By 
the time the secondary lesions appear the serologic tests are reactive in 
almost every case and remain so during the latent stage. In the presence of 
a positive darkfield reading, only the standard serologic tests, including a 
quantitative test, need be performed in primary and secondary syphilis. 
In situations in which the clinical symptoms and signs may be confused, 
and the darkfield examination does not reveal the organism, the treponemal 
tests are needed for final evaluation. It is important to point out that the 
titer per se of reactive serologic tests gives no clue as to the status of 
infectiousness when unaccompanied by clinical information. Doses of 
antibiotics inadequate for cure of syphilis if given during the incubation 
period or during the first week of primary syphilis often delay the appear- 
ance of reactive serologic tests beyond the usual time. 



632 Harry Pariser 

DIFFERENTIAL DIAGNOSIS 

This presentation would inevitably be bogged down in a morass of 
detail if an attempt were made to go into detailed descriptive differential] 
diagnosis. All of the diseases to be considered have wide variations in 
clinical manifestations and are adequately described in detail in standard 
textbooks or articles. 

A list of the diseases to be considered in differential diagnosis may be 
helpful as a guide. In the differential diagnosis of primary syphilis, the 
following diseases are to be considered: chancroid, granuloma inguinale, 
carcinoma, tuberculosis, lymphogranuloma venereum, trauma, herpes pro- 
genitalis, lichen planus and drug eruptions. 

Extragenital lesions require, in addition, differentiation from am 
disease capable of producing a lesion with satellite lymphadenopathy, sucl 
as tuberculosis, sporotrichosis, tularemia, herpes, amelanotic melanomj 
and cat scratch fever. 

Diseases to be considered in differential diagnosis of secondary syphili 
include pityriasis rosea, lichen planus, psoriasis, seborrheic dermatitis 
fungous (trichophyton) infection, tinea versicolor, infectious mononucleois 
erythema multiforme, drug eruptions and various exanthemata. Such rar ! 
conditions as pityriasis lichenoides chronica, urticaria pigmentosa, sarcoid 
mycosis fungoides and granuloma annulare with multiple lesions at time 
need to be considered. Extracutaneous involvement such as iritis, alopeci 
and sore throat introduce a host of other etiologic possibilities. 

It is important to keep in mind the possibility of co-existence of tw 
diseases, e.g., syphilis and another disease. In addition, one should not fa 
into the error of assuming that all the presenting pathologic findings ai 
syphilitic because serologic tests are reactive. If presumably infectioi 
syphilitic lesions do not heal promptly following treatment (i.e., within 
week) coexisting diseases should be suspected. 



EPIDEMIOLOGIC CONSIDERATIONS 

The physician's obligation is by no means completed when he diagnos 
and treats his patient who has infectious syphilis. If control of syphilis! 
to be achieved, it is mandatory that contacts, both source and possit i 
spread, be examined. Best epidemiologic results will be obtained if ti^ 
physician utilizes the specialized skills of health department epidemiologic ; 
whose services are readily available. The physician should regard 1 5 
diagnosis of infectious syphilis as a public health emergency and shoil 
contact the health department on the same day that the diagnosis is mac 
If the patient's diagnosis is primary syphilis, all possible source contai 
up to three months prior to the appearance of the lesion should be exa 
ined, and if secondary or early latent syphilis, for a 6- to 12-month perill 



PLATE II 



Fig. 18. Patient assumed these papular 
lesions, which proved to be syphilitic, 
occurred as result of cutting himself 
while shaving. 



Fig. 19. Syphilitic eruption of face of 
5 to 6 da3's' duration. Patient assumed this 
was acne. 





Fig. 20. Complete examination re- 
vealed syphilitic vulvar lesions which 
patient (Fig. 19) denied existed. Both areas 
cleared promptly with treatment. 



Fig. 21. Raised erosive syphilitic lesion 
of the nipple. 



Infectious Syphilis 633 

prior to diagnosis. It is estimated that 40 to 60 per cent of syphilitic 
patients pass through their primary and secondary stages unaware of or 
ignoring signs and symptoms as inconsequential. This is the group that it 
is important to reach if we are to make inroads on the incidence of the 
disease and only by the epidemiologic approach will they be brought to 
examination. When darkfield examinations are performed on any lesions 
present in such contacts, no matter how ''atypical" in appearance, we 
begin to realize the wide variations in the manifestations of infectious 
syphilis. At times the organism will be found in lesions so ''atypical" that 
even experienced clinicians would not have considered the possibility of 
syphilis. One shudders to think how often these "atypical'' lesions, dark- 
field positive, are ignored by the patient or misdiagnosed by the physician 
(Figs. 14 to 21). 

Since syphilis is transmitted only by contact with a lesion, the patient 
with infectious syphilis must have been exposed at least three weeks before 
(the incubation period) to a contact having an infectious lesion. Therefore, 
when examining this source contact one should expect to find serologic and 
possibly clinical evidence of syphilis. In the presence of lesions the diag- 
nosis, of course, can be established promptly by darkfield examination. In 
the absence of lesions a fast standard flocculation test should be performed. 
A quantitative VDRL test or one of its modifications can be done by a 
cooperative laboratory one-half to one hour after the specimen is received. 
A reactive test in a source contact is considered adequate for the diagnosis 
of infectious syphilis from an epidemiologic point of view even though no 
lesions are present. Under these circumstances the diagnosis and treatment 
of the source contact may be completed in one session. From a clinical 
point of view, the diagnosis of infectious syphilis is only presumptive in 
the absence of lesions. If facilities are not available for fast testing or if the 
contact history is unreliable, treatment may be given purely on an epi- 
demiologic basis. If all the named source contacts show no lesions and 
have repeatedly nonreactive serologic tests, it is apparent that the epi- 
demiologic information is inaccurate or inadequate. 

An individual exposed to infectious syphilis will not show clinical 
evidence of the disease for at least three weeks and serologic evidence for 
four to six weeks. 

Opinions at this point are divided as to whether or not to treat on 
purely epidemiologic evidence or to follow this spread contact until a defi- 
nite diagnosis is established or rejected. The promiscuous group or those 
difficult to follow are usually treated on an epidemiologic basis, and contact 
information is obtained and utilized. Every attempt is made to establish a 
diagnosis. If clinical diagnosis is deemed desirable, serologic testing should 
be continued for at least three months after the last sexual exposure before 
the diagnosis is rejected. Diagnosis of infectious syphilis can fairly safely 
be presumed in a patient who is a contact of a proven case and who shows 
a rapidly rising titer but no apparent lesions. It should be emphasized that, 



634 Harry Pariser 

if only a definite spread contact (e.g., husband to wife) is brought to treat- 
ment, the epidemiologic investigation is incomplete. There must always be 
a source. 

While syphilis is transmitted primarily by heterosexual means — male 
to female — we have recently become aware of the fact that homosexual 
transmission may be as frequent among certain groups as heterosexual 
transmission. In the homosexual group with a venereal disease, there is as 
a rule a considerably greater degree of promiscuity than in the heterosexual, 
and the number of contacts named per case is two to three times that 
named by the heterosexual. Kissing in the presence of oral lesions or 
abnormal sexual practices (genitobuccal contact) may account for more 
infection than is generally suspected. 



TREATMENT 

Paradoxically, the very effectiveness of modern treatment if given in 
the primary and secondary stages of syphilis, and to a lesser extent in 
early latency, denies the patient the opportunity to develop significant 
immunity against the organism. When an infectious type of lesion appears 
after treatment, this is usually a manifestation of reinfection, rather than 
relapse. Rigid differentiation between relapse and reinfection is often 
difficult. 

Any of the following treatment schedules given intramuscularly can 
be expected to achieve a chnical cure in 92 to 95 per cent of infectious 
syphiUtic patients. Fortunately there is no evidence to show that Treponema 
pallidum is capable of developing resistance to penicillin. 

1. Benzathine Penicillin G (Bicillin). 2.4 million units given at 
one session by injection into two to four sites (2 to 4 cc. per injection). 

2. Procaine Penicillin G in Oil with 2 per cent Aluminum 
MoNOSTERATE (PAM). 4.8 million units given in doses of 1.2 million 
units twice weekly for two weeks, or 2.4 million units for the first dose 
and 1.2 million units for two additional doses with an interval of three to 
four days. 

3. Aqueous Procaine Penicillin G. 4.8 million units given in 
daily doses of 600,000 units for eight injections. 

The first schedule has the advantage that it can be completed in one 
session. 

To check efficacy of treatment in a specific case, the following routine 
serologic information is essential, in addition to darkfield examination : 

1. Pretreatment serologic tests including at least one quantitative 
reading. For this purpose flocculation tests (VDRL, Mazzini, KUne, etc.) 
are usually employed. 

2. Post-treatment quantitative tests monthly for six to nine months 
and every three months thereafter for a total observational period of at 



Infectious Syphilis 635 

least two years. A satisfactory outcome can fairly confidently be predicted 
if the post-treatment serologic tests show progressively lower titers over a 
period of three to nine months and remain nonreactive or low titered over 
the rest of the observational period. Usually the tests become nonreactive 
or low titered earlier in primary than in secondary syphilis and, if non- 
reactive before treatment (seronegative primary syphilis), remain so after 
treatment. The later in the early latent stage that treatment is started the 
more likely are the quantitative titers to be unchanged by treatment. 

Slight fluctuations in the low titered range (e.g., 1 to 4 dils) should 
not be cause for alarm since such variations may indicate only varying 
sensitivity of the antigen and/or difference in laboratory interpretation. A 
variation of significant degree which is confirmed (two-tube dilution or 
more, e.g., 4 to 16 dils or 16 to 64 dils) indicates either relapse or reinfection 
and may or may not be associated with the appearance of lesions. In most 
cases a rapid rise in titer is due to reinfection. If relapse is suspected, the 
schedule should be doubled, whereas in reinfection the original treatment 
schedule should be repeated. 

For those patients who are sensitive to 'penicillin, the ''mycin" drugs 
may be substituted. Experience with these drugs is not nearly as extensive 
as with penicillin. The following schedules are probably adequate : 

Tetracycline. Two grams daily in divided doses of 500 mg. four 
times daily over a period of 15 days for a total of 30 grams. 

Erythromycin. Two grams daily in divided doses of 500 mg. four 
times daily over a period of ten days for a total of 20 grams. 

The above schedules need more evaluation before they can be as 
universally accepted as the penicillin schedules, and represent minimum 
dosages. Follow-up should include spinal fluid examination. Generally 
speaking, the "mycins" are not as effectively treponemicidal as penicillin. 



COMMENT 

I would like to conclude this discussion of infectious syphilis with a 
plea. An accurate history of possible exposure, onset manifestations, pre- 
vious verified serologic tests or possible treatment is essential for evaluation. 
We must realize that infectious syphilis is a disease primarily of signs 
and very few symptoms. We will have two strikes against us unless the 
patient is examined completely stripped. To find syphilitic lesions we must 
snoop around corners so to speak; that is, spread the vulva and buttocks, 
pull back the foreskin, stretch the scrotum, evert the lips, check the 
mucous membranes carefully, examine the skin by cross light, pay par- 
ticular attention to the palms and soles, the sides of the nose, the corners 
of the mouth, and palpate for the presence of adenopathy. We must 
realize that the manifestations of primary and secondary syphilis are so 
varied that the best we can do clinically is to make an educated guess as 



636 Harry Pariser 

to the diagnosis, sometimes with almost 100 per cent assurance and at 
other times with considerably less certainty. Appropriate laboratory tests 
are absolutely essential to confirm or reject the clinical impression. Any 
eruption not typical of a given disease should be investigated for the 
possibility of syphilis. We should constantly check the impulse to rule out 
the possibility of syphilis in the well-dressed and well-educated purely on 
socio-economic considerations, to regard every eruption as syphilitic in 
the venereal disease clinic and, by contrast, to ignore the possibility of 
syphilis in other clinics and in our private offices. | 

403 Medical Tower 
400 Gresham Drive 
Norfolk 7, Virginia 



The Importance of Contact Investigation 
in the Control of SyphiHs 

WILLIAM W. FRYE, Ph.D., M.D.* 



Following the introduction of penicillin as a therapeutic agent 
and the proven susceptibility of Treponema pallidum to this antibiotic, 
practically all involved in the control of syphilis were convinced that it 
would be only a matter of time until this disease would be eradicated. 
Unfortunately treatment alone has not achieved the ideal, and the decline 
of new cases of syphilis in the United States ended in about 1955. Since 
then early infectious cases of syphilis have been reported in increasing 
numbers, from all areas and in practically all social groups. 

The belief in penicillin as a method of eventual eradication of the dis- 
ease was so absolute that there was actually damaging de-emphasis of the 
epidemiologic methods developed during the past three decades in the 
control of syphilis. This de-emphasis extended from our medical schools 
and teaching hospitals to the offices of the practicing physicians and to 
the departments of health. The marked reduction in financial support for 
the treatment and control of the venereal diseases extended from the 
national to the local levels in almost every area of the United States. The 
attitude of the public has also contributed to this increase in the disease in 
that the average citizen depends upon penicillin to take care of any of his 
indiscretions. The importance of venereal disease education, especially for 
young people, has not been appreciated by some. The number of teen-agers 
and young adults diagnosed and reported as having primary and secondary 
syphilis over the past few years is alarming. It was recently stated that 
more than 50 per cent of all the reported cases of infectious syphilis occurs 
among teen-agers and young adults under 25 years of age. It is apparent 
that during the past decade a generation of young people have grown up 
completely unaware and ignorant of venereal diseases. Almost too late, we 
are forced by circumstances to recognize the fact that it will take more 
than a ''miracle drug" to control syphilis and the other venereal diseases. 



Vice-President, Louisiana State University, and Dean of its School of Medicine, 
New Orleans, Louisiana; Chairman, Combined Dean's Committee, Veterans 
Administration Hospitals; U.S.P.H.S. Advisory Committee on Allergy and Infec- 
tious Diseases; Member, Armed Forces Epidemic Board on Enteric Diseases, 
Washington, D. C. 

637 



638 



William W. Frye 



THE GROWING SERIOUSNESS OF THE PROBLEM OF CONTROL 

The seriousness of this problem can be illustrated by a review of 
reported cases of infectious syphilis (primary and secondary) in the State 
of Louisiana. The trend for the state and for the City of New Orleans over 
a period of five years, 1958 through 1962, is shown in Figure 1. The early 
downward trend of infectious cases reported was followed by a rapid rise 
and the most marked increase occurred in 1961. It was noted that 32 per 
cent of the total number of primary and secondary cases occurred in 
teen-age or young adults, 20 years of age or younger. The number of cases 
of primary and secondary syphilis reported in the United States from 1957 
through 1961 increased by 334 per cent. By comparison, the actual number 
of reported cases of acute syphilis from 1958 through 1961 in the City of 
New Orleans increased from 24 to 770. A portion of this increase was due 
to renewed efforts on contact investigation in the health department. 

In a neighboring state, an outbreak of acute syphilis was uncovered 
primarily among teen-agers. This demonstrates the importance of contact 
investigation in uncovering an epidemic of syphilis. There were 141 indi- 
viduals involved. The average age in this group was 19.7 years and the 
average age of those found infected was 18.4. Thirty-four cases of syphilis 
and two of gonorrhea were diagnosed and treated. Five of the infected 
persons brought under treatment attended elementary school. Their ages 
were 6, 10, 12, 13 and 15 years. Twelve more infected individuals attended 
high school. The youngest person brought to treatment was a child six 
years of age having secondary syphilis. 

It is evident from the reporting throughout the entire country that 
the reservoir of infectious syphilis is increasing. The human host, of course, 
is the sole transmitter of this communicable disease. It is also apparent 



Acute Cases of Syphilis 
Primary 8 Secondary 



1600 



1516 




1958 1959 I960 1961 1962 

Reported to the Louisiana State Board of Health 
over a 5 Year Period, 1956-63. 

Figure 1. 



Importance of Contact Investigation in Control of Syphilis 639 

that determination of sources of infections and the follow-up of contacts 
have not received the emphasis necessary to control the spread of syphilis. 



PRACTICALITY OF EPIDEMIOLOGIC METHODS IN THE CONTROL 

OF SYPHILIS 

The known contacts of individuals with an infectious disease — persons 
from whom the infection may have been acquired and to whom the disease 
may have been transmitted — theoretically form the most logical group in 
which to search for new and unknown cases of any communicable disease. 

Since the early studies of syphilis in Europe, it has been recognized as 
a communicable disease. Ignorance, superstition, moral issues and fear 
combined to retard the general progress of medical science in finding 
effective methods of control of the venereal diseases. In spite of these 
handicaps, within a span of only one century, by clinical observation alone, 
three distinct modes of transmission of syphilis were proved. These were 
genital, extragenital and hereditary. 

Syphilis, even though it is considered to be a highly infectious disease, 
is not always communicable. However, like some other chronic infectious 
diseases, syphilis often remains communicable for long periods of time, 
though there are even longer periods when the disease is probably noncom- 
municable to intimate contact. 

Epidemiologic studies of syphilis present a series of typical pictures of 
outbreaks, some small, involving two or three persons, others compara- 
tively large, considering that acquired syphilis is spread almost exclusively 
by intimate contacts and that congenital syphilis is transmitted only from 
the pregnant woman to her fetus. 

Certain types of epidemiologic investigations in syphilis were for many 
years considered impossible owing to the modes of transmission which are 
usually associated with intimate relationships between persons and the 
lack of effective methods of approach to exposed individuals. In com- 
municable diseases such as tuberculosis, typhoid fever, diphtheria and many 
others, public health investigators have no hesitancy not only in searching 
out exposed individuals, but also in keeping such individuals under investi- 
gation for a sufficient period of time to determine whether or not they are 
infected. 

It was not until the early 1930's that the same principles of epidemio- 
logic methods, such as contact investigation, were applied in case finding 
in syphilis. Parran (1932) called attention to the lack of interest on the 
part of epidemiologists in the use of epidemiologic principles in syphilis 
I control. Munson (1932) demonstrated, by tactful and persistent investiga- 
tion of contacts of acute cases, that syphilis appears in a community as 
localized epidemics originating from one or more sources of infection, and 
that each infected person is potentially a focus of an epidemic. Almost 



640 William W. Frye 

immediately, the value of such contact investigations were recognized in 
the control of venereal diseases. 

The paper published by Munson (1932) on "Practicability of Epidem- 
iological Methods in the Control of Syphilis," is of historic interest in that 
he stimulated the use of the epidemiologic approach in the control of 
syphilis. He stated that the control of syphilis is predicated upon three 
very distinct factors: (1) early and accurate diagnosis; (2) early and proper 
treatment and (3) ''sole-leather" epidemiology. He was convinced that 
failure to control syphilis was definitely due to the fact that the cases were 
not properly investigated along practical epidemiologic lines. Some of the 
statements made in his published paper deserve repeating here, and I 
quote: ''May I preface some narratives which I wish to give you by stating 
what may be my feeling concerning epidemiologists and epidemiology? An 
epidemiologist is that creature who curiously combines a reasonable scep- 
ticism and insatiable curiosity with a passion for the truth and has the 
ability to recognize the truth when it looks him in the face, and with all 
this has the initiative to apply sufficient sole leather to the job to get the 
facts. If we are going to control syphilis we must go to work instead of 
talking about it. If every case of syphilis were investigated and proper 
attention paid to contacts, as is done with other communicable diseases, it 
would not be very long before medical students would have difficulty in 
obtaining clinical material enough for instruction in this disease. There is 
just one conclusion: Every case of syphilis should have a hard-boiled, 
determined and bold epidemiological investigation." He then documented 
his thesis by detailing a number of contact investigations under several 
different circumstances. 

A few individuals following Munson's lead began to use contact 
investigation as a method of case finding. It was recognized that the facts 
necessary for an effective epidemiologic attack on syphilis were known. 
The only thing necessary was a practical application of the information at 
hand. It was also learned that sources of infection can be determined since 
only a few persons are usually involved. Elaborate investigation is, how- 
ever, often necessary in the contact investigation of venereal diseases, and 
contact investigation requires a considerable amount of skill, tact and 
patience. 

It has been clearly demonstrated over the past ten years that methods 
to discover reservoirs of infection must be instituted before the control and 
possible eradication of syphilis can be obtained. These reservoirs are com- 
prised of untreated and inadequately treated individuals with syphilis. 
Man in this case is his own worst enemy, since man alone is the reservoir 
and the only source of infection in this disease. 

TECHNIQUES OF CONTACT INVESTIGATION 

Extensive studies in the epidemiology of syphilis were begun at the 
syphilis clinic at the Vanderbilt University Hospital in early July, 1937. 



Importance of Contact Investigation in Control of Syphilis 641 

Certain preliminary studies had been made prior to this time but the 
intensive studies in contact investigation were instituted in connection 
with the estabhshment of a four-weeks' postgraduate course in syphiUs 
control (Kampmeier and Clark, 1939). This short course of instruction in 
syphilis control was designed for county health officers and private physi- 
cians, cooperating with local health departments, public health nurses and 
social workers. The syphilis clinic at Vanderbilt Hospital was organized as 
a special clinic in the Department of Medicine during 1926 and had been 
concerned only with instruction of undergraduate students and residents 
(Kampmeier, 1938). The chief objective of this four- weeks' postgraduate 
course was to provide an opportunity for a period of intensive instruction 
in diagnostic and therapeutic procedures, with the major effort being 
placed on case finding, contact investigation, case holding and the broad 
public health aspects of syphilis control (Frye, Kampmeier and Keller, 
1942). Contact investigation had been proved to be one of the most 
productive methods of case finding by Dr. E. Gurney Clark, the clinic 
epidemiologist, and others working in the syphilis clinic (Clark, 1940). 
Each student was given detailed instruction in methods used in contact 
investigation and each was assigned contacts to trace. 

Owing to the importance of the methods of contact investigation at 
the present time, and the fact that the needs in this area are so important, 
these methods will be described in some detail. 

Successful contact investigation begins with securing the cooperation 
of the patient who has been found to have early infectious syphilis (Sweeney, 
1942). The patient is instructed by his physician concerning the nature of 
his illness, the treatment necessary, and the precautions which must be 
followed to prevent the spread of the disease. Usually the examining 
physician has discussed with the patient the need for contact examination 
and has explained in detail how the disease may be spread from one person 
to the others. The physician in his first contact with the patient has laid 
the groundwork for the obtaining of additional information by the epi- 
demiologist, the public health nurse and the social worker. 

Speed is of the essence in contact investigation in syphilitic control. 
Success in obtaining the names of extramarital sexual contacts of patients 
with early syphilis depends primarily upon securing the complete coopera- 
tion of the patient immediately after the diagnosis is made. The well 
[informed, tactfully handled patient is usually willing to give detailed 
^information. The method of obtaining the names of the contacts has a 
general basis that must be adapted to fit the individual situation. Patients 
can usually be persuaded to name and to allow visits to be made to con- 
tacts, in most cases, provided they can be assured that their names will 
not be revealed to the contacts. Visits to contacts can be facilitated by 
collecting in advance as much information as is possible about that indi- 
vidual or that particular contact. The general method of approach to sexual 
contacts differs somewhat according to the age, marital status, economic 



642 William W. Frye 

situation, and position of the contact. The success of the interview with 
the contact depends largely on securing the confidence of that individual 
immediately, employing sufficient simple instruction, and in satisfactorily 
answering the usual question as to who gave his name or her name. Marital 
problems created by the diagnosis of syphilis in one or both marital partners 
are frequently serious but can usually be worked out on an individual basis 
if tactful assistance is promptly given. In most instances, the patient with 
syphilis can be of assistance in bringing in his own household contacts for 
examination. It must be re-emphasized here that the period of time between 
the diagnosis of syphilis in the original patient and the examination of 
contacts is extremely important in preventing the spread of syphilis. 

It has been proved beyond question that, of the various methods of 
case finding, contact investigation is the most direct epidemiologic approach 
and offers the best opportunity for discovery of early infectious cases. In 
contact investigation, attention must be focused primarily upon the pa- 
tient. The patient is the key to success. Direct questioning as to sexual 
intimates should follow careful explanation of the disease and adequate 
consideration of the patient's immediate problems, such as telling the 
family or interpretations to the marital partner. Names of extramarital 
sexual contacts are readily obtained when properly sought. The handling 
of teen-agers and their parents and contacts is a very difficult problem and 
needs a seasoned interviewer and contact investigator to handle it. 



RESULTS— THE FINAL CRITERIA 

A few examples of what can be accomplished with contact investigation 
will help to illustrate the success which has been obtained by this epidemi- 
ologic procedure. These examples of case investigations will serve to illus- 
trate the practical aspect of the various procedures which can be used in 
the application of epidemiologic measures in the control of syphilis. 

Figure 2 is of historical interest here since Smith and Brumfield (1933) 
were among the first to demonstrate the value of contact investigation and 
to prove the practical application of the epidemiologic method. This is an 
example of the discovery of a small epidemic, which if not investigated! 
could have led to many more infectious cases of syphilis. Here these 
investigators presented a new method in the control of syphilis. They also 
demonstrated that it is practical in all classes of patients to trace the 
source of infection and to bring the sources under treatment. 

Figure 3 is unusual in that the investigation originated as the result 
of finding a white infant with acquired secondary syphilis. The father 
mother and one other member of the household were found infected 
Fourteen persons in all were investigated. Ten adults were found to have 
syphilis, six of whom were in the infectious stage of the disease. 



MPORTANCE OF CoNTACT INVESTIGATION IN CoNTROL OF SyPHILIS 643 

Contacts of a Syphilitic 
Patient 

Initial easel*. 

R.M.(MrsG.R.) 



Iek.UjbIJerUe.d.Uj.m. 

I 



• Chancre 
iii! Secondary 

iTMrs E.R. 



redrawn from Smith and Brumf ield 

Figure 2. 



Investigation of Contacts of Infant 
with Secondary Syphilis 

"11^ Household group 

0«OfiO 

Father 



in household Father Mother 



1 y^y^"^« 

Fother Brothers Source 

Poresis ± i i 

tot 

me Wife Mother 

n /\ El Early syphilis 

Children r J f J ■ Late/unknown durof ion 

\j \J D Not infected 

GO Not infected 



redrown from Kontpmeier 

Figure 3. 



644 William W. Frye 

Investigation of Contacts of WF with 
Breast Ctiancre 



I 



Child ■ ■ Husband 
Grandmother ■ n «!? ill-. 



* 



D not infected 



00 i t* 



Husband 



redrawn from Kompmeier 

Figure 4. 



Figure 4 shows the results of an investigation of contacts of a white' 
female seen for chancre of the breast. This patient had acquired syphilis^ 
from nursing her child who had secondary lesions in the mouth. Eightl 
persons were examined and six were found to have syphilis. The grand- 
mother, who was found to have secondary syphilis, had nursed the child. 
The grandmother had been infected by her husband and her own child hadil 
been infected after nursing her. Of the six individuals found to be infected, ,i 
three were children with acute syphilis, two of whom had become infected I 
through nursing and the third had acquired the disease through ''second- 
hand" chewing gum. 

Figure 5 is an illustration of an outbreak of syphilis discovered in a 
rural county in Tennessee. This investigation helps to illustrate several! 
important points. The index case was that of a young, white male who 
developed acute syphilis while he was a member of the Civilian Conserva-^ 
tion Corp. He was given a few injections of neoarsphenamine and bismuth 
and discharged from the CCC. He was told upon discharge to report to 
the county health officer, who would arrange for continuation of his treat- 
ment. He failed to do this and, approximately four months later, developed 
an infectious relapse. He then went to a private physician for treatment. 
During his relapse, he had sexual contact with three prostitutes, each oi 
whom developed acute syphilis. The physician reported the original case 
to the health department. The health department personnel and the 



Importance of Contact Investigation in Control of Syphilis 645 

practitioner were able to trace 36 contacts, 30 of whom were found to have 
syphihs. This study illustrates the dangers of inadequate treatment, and 
the necessity of reporting promptly those persons with acute syphilis who 
have not had adequate treatment or who leave one area to reside in 
another. This also illustrates the importance of the practicing physician in 
the control of syphilis. 

Clark (1939) described an epidemic discovered and brought under 
control in the routine management of patients in the syphilis clinic at 
Vanderbilt Hospital. A young Negro girl came to the clinic because of 
early syphilis of the skin and mucous membranes. When she learned the 
lesions were due to syphilis and were highly infectious and that she had 
doubtless exposed others to the disease, she disclosed the names of eight 
young men with whom she had had sexual intercourse. She also agreed to 
assist in persuading her contacts to have an examination. All of the sexual 
contacts and six members of her family were examined, either by their own 
physicians or in the syphilis clinic. Of these 14 persons, nine were found to 
iiave syphilis, five of whom were in the infectious stage. A sister was totally 
unaware of her infectious lesions, and because of this it was a simple matter 
bo develop in her a sympathy for her contacts, who might have no knowl- 
edge of the lesions. She designated four sexual contacts, three of whom 
;vere found by their own physician to have infectious or potentially infec- 
nous syphilis. Subsequent examination of other contacts related to this 
pidemic disclosed four additional cases of early syphilis and was instru- 
nental in returning two old cases to treatment. In this epidemic, 18 cases 
)f syphilis were found among 32 persons designated as contacts. Most of 
ihese were totally unaware of the fact that they had syphilis or that they 
lad been exposed to syphilis. 

Outbreak of Syphilis in Monroe County, Tenn. 

■ Transient boy 



Prostitute Prostitute B^.^^^^^^^ Prostitute 



• ■Wife /■ WifeAwifeHB 

» /TDaughterW YW 

i /A i i 



D Negative 
^ Sexual intercourse 
•— Family/household contacts 
Congenital infection 



'd Date from Kimbrough, Cowgill, ond Bowerman^ Madi$onville,Tenn. 

(hi i Figure 5. 



646 



William W. Frye 



Congenital Syphilis 



Mother 



Death from 
syphilis reported 



« 



■ Positive 
D Negative 



I — I — r 



Father 



1 — I — I 



t« Mf f 



21 



19 



14 



13 



II 



7 years 



Data from New York City Heoitti Department. 



Figure 6. 



The results of epidemic investigations conducted by Clark (1940) in 
the Vanderbilt University Hospital Clinic are of great interest in pointing 
out what can be and was accomplished when the contacts of acquired 
syphilis were studied carefully. In a series of 204 cases of primary or 
secondary syphilis, 387 sexual contacts were named. Of that number, 343 
or 88.7 per cent were examined. Of the 343 sexual contacts examined, 258 
or 75.3 per cent were found to have syphilis. In the latter group of 258 pa- 
tients, 213 or 62 per cent were found to have infectious or potentially 
infectious syphilis. The group of 213 persons included 147 or 42.8 per cent 
with primary or secondary syphilis, 46 with early, latent syphilis, not 
previously diagnosed, and 20 patients with early latent syphilis, previously 
diagnosed but inadequately treated cases. Thus for each 100 original 
patients, 104 additional patients capable of transmitting syphilis were 
brought under treatment as the result of the application of epidemiologic 
procedures. It is obvious that more acute cases of syphilis will be discovered 
among sexual contacts than will be found among other groups of exposed 
persons. Among 365 nonsexual family contacts of 520 patients with latent 
syphilis or late syphilis, ten cases of infectious or potentially infectious-! 
syphilis were discovered. 

Congenital syphilis must be distinguished from syphilis contracted at 
or soon after birth. It is an infection acquired during fetal Ufe. Thus every 
pregnant mother must have a complete examination, including serologic 
tests for syphilis. In fact, practically all states require by law at least one 
blood test during pregnancy. Congenital syphilis is preventable and, if the 
disease is acquired during pregnancy, early diagnosis and treatment will 
prevent fetal infection. The wisest procedure to follow when infection ii: 



Importance of Contact Investigation in Control of Syphilis 647 

the mother is suspected but unsubstantiated is to examine the mother, 
both early and late in pregnancy, and to follow the mother serologically 
and both the mother and child clinically after birth. 

Figure 6 illustrates the fact that syphilis may be transmitted from 
mother to fetus over long periods of time. Fetal deaths from syphiUs may 
occur at any time but are more likely to occur during the early and early 
atent stages of the disease in the mother. As is illustrated in this family 
infection, the father was not infected. All but one child born during a 
period of over ten years was infected. Here again the importance of appli- 
cation of the epidemiologic principles in diagnosis and prevention of 
congenital syphilis are obvious. 



A PRACTICAL PROGRAM FOR THE FUTURE 

Early in the campaign against syphilis in the United States, it was 
demonstrated that the application of epidemiologic methods in the preven- 
tion and in the control of this disease is practical. The epidemiologic 
methods must be applied by official health agencies as a part of the program 
"or the prevention and control of this communicable disease. The medical 
md public health personnel should be responsible for case investigation. If 
contact investigators are properly trained, tactful and conscientious, there 
should be no more difficulty in conducting successfully a syphilis case 
finding program than there would be in the case of tuberculosis, or any 
)ther communicable disease. 

There was a period of almost two decades when, because of the 
difficulties of treatment and follow-up, syphilitic patients came to be 
landled principally by specialists — the bulk being diagnosed and treated 
n public health facilities. 

Now largely because of the development of penicillin therapy, but for 
3ther reasons as well, the pendulum has swung again, and the general 
If 3ractitioner is seeing an ever-increasing proportion of acute infectious 
yphilis or persons suspected of being infected. The important role of the 
e<J )rivate physician and his increasing interest in the venereal disease problem 
s indicated by the fact that in 1958 only 3.2 per cent of all primary and 
secondary cases were reported by private physicians, the remainder being 
eported from public health clinics. Two years later, this picture had 
changed and in 1960 private physicians reported 25.9 per cent of the total. 
The services of public health venereal disease investigators, who are 
especially trained in the technique of interviewing and contact tracing, are 
available to private physicians in many areas and particularly in larger 
:ities. When we consider that every case of syphilis diagnosed represents 
it least one additional case, that in the person from whom the infection 
vas acquired, plus perhaps one or more additional persons whom the 
)atient in turn may have infected, we realize the importance of rapid and 



648 William W. Frye 

thorough epidemiologic investigation and treatment of every known case 
of infectious syphiUs. Only in this way can the chain of infection be broken 
and this is the area in which the trained venereal disease investigator can 
be of assistance to the private physician. 

The control and ultimate eradication of syphilis can be attained, if 
the fundamental requirements for its control as an infectious disease are 
satisfied. Increased awareness of its prevalence, expert application of diag- 
nostic measures, adequate treatment, epidemiologic investigation and pro- 
fessional and lay education, all put to use in one common effort will make 
it possible to attain our goal. 

We are no longer dependent upon investigations to demonstrate the 
value of contact investigation as a case finding method. Dr. Kampmeier, 
whom we are honoring today, his colleagues, and his many students, both 
graduate and undergraduate, have been pioneers in the appUcation of the 
epidemiologic method in venereal disease control. 

We now know the cause and mode of spread of syphilis. We have the 
means and skills for its diagnosis. We have in our possession an effective 
therapeutic agent. We know enough about its epidemiology to warrant 
unusual effort for its control. It has been clearly demonstrated that syphilis 
cannot be controlled by treatment alone. Let us now shape our program 
to the problem. 



REFERENCES 

Ball, R. W.: Epidemiology of syphilis; report on 2 chains of infection. J. South Carolina 

M. A. 52: 361-366, 1956. 
Brown, W. J.: United front in VD control. Arizona Med. 16: 427-429, 1959. 
Brumfield, W. A., Jr. and Smith, D. C: Transmission sequence of syphilis. Am. J. Pub. 

Health & the Nation's Health 21^: 576-580, 1934. 
Clark, E. G.: Epidemic syphilis — its recognition and management. Ann. Int. Med. IS: 

238-247, 1939. 
Clark, E. G.: Studies in the epidemiology of syphilis. Epidemiologic investigations in a 

series of 996 cases of acquired syphilis. I. Material on which epidemiologic studies 

are based. II. Contact investigation in a series of 824 patients with syphilis. 

Ven. Dis. Inform. 21: 349-369, 1940. 
Clark, E. G. and Kampmeier, R. H.: Contact investigation and the early recognition 

of syphilis. Urol. & Cutan. Rev. I^S: 169-170, 1939. 
Cowper, H. H. and Clark, E. G.: Studies in the epidemiology of syphilis. IV. The 

value of patient education in controlling the spread of syphilis. Ven. Dis. Inform. 

22: 7-11, 1941. 
Dougherty, W. J.: Epidemiologic treatment of syphilis contacts. J. M. Soc. New Jersey 

59: 564-567, 1962. 
Emerson, Haven: Administrative Medicine. New York, Thomas Nelson & Sons, 1941. 
Fiumara, N. J., Segal, J. and Jolly, J.: Contact investigation; combined military- 
civilian program. Pub. Health Rep. 68: 289-294, 1953. 
Frye, W. W., Kampmeier, R. H. and Keller, A. E.: Training of medical personnel in 

syphilis control. Am. J. Pub. Health 22: 495-502, 1942. 
Gray, A. L., Iskrant, A. P. and Hibbets, R. S.: Contact investigation in rural county in 

Mississippi. Ven. Dis. Inform. 50: 165-169, 1949. 



Importance of Contact Investigation in Control of Syphilis 649 

Kampmeier, R. H.: The teaching of syphilis to undergraduates and postgraduates. 
South. M. J. 31: 218-222, 1938. 

Kampmeier, R. H. and Clark, E. G.: A four-week postgraduate course in syphilis con- 
trol. Ven. Dis. Inform. 20: 153-156, 1939. 

Kampmeier, R. H.: Essentials of Syphilology. Philadelphia, J. P. Lippincott Co., 1943. 

Kimbrough, R. C, Cowgill, D. M. and Bowerman, E. P.: Rural syphilis — a localized 
outbreak. Am. J. Pub. Health 28: 756-758, 1938. 

Klingbell, L. J. and Clark, E. G.: Studies in the epidemiology of syphilis. III. Conjugal 
syphilis. A statistical study of a series of 226 married persons whose spouses were 
examined. Ven. Dis. Inform. 22: 1-6, 1941. 

Lugar, Robert: The epidemic chain. Arizona Med. 16: 425-426, 1959. 

Munson, W. L.: Practicability of epidemiological methods in the control of syphilis. 
Am. J. Pub. Health & the Nation's Health 22: 134-140, 1932. 

Nelson, N. A.: The control of syphilis from the health officer's viewpoint. Am. J. Pub. 
Health & the Nation's Health 22: 165-173, 1932. 

Parran, Thomas, Jr.: Syphilis from the epidemiologist's point of view. Am. J. Pub 
Health & the Nation's Health 22: 141-156. 

Smith, D. C. and Brumfield, W. D.: Tracing the transmission of syphilis. J. A.M. A. 101: 
1955-1957, 1933. 

Sweeney, Anne: Studies in the epidemiology of syphilis: V. Methods of contact investi- 
gation. Ven. Dis. Inform. 23: 137-143, 1942. 

Webster, B. and Shelley, E. I.: Studies in the epidemiology of primary and secondary 
syphilis in New York City. Am. J. Pub. Health 31: 1199-1205, 1941 . 

1542 Tulane Avenue 

New Orleans, Louisiana 70112 



DISCUSSION 
By William J. Brown, M.D., Atlanta, Georgia 

There are two comments I would like to make concerning Dr. Frye's 
paper. The first concerns an extension of the technique of contact investi- 
gation in the epidemiology of early infectious syphilis and the other 
concerns the problem which exists in the widespread application of epi- 
demiology to early infectious syphilis. 

Contact investigation, which I am convinced has been proved to be a 
necessary technique in epidemiologic control, becomes an even more 
productive and effective technique when it is expanded to include the 
syphilitic patient's friends and social group members. This expansion of 
contact investigation, which was recently evaluated by eight states in the 
epidemiology of 1256 early infectious syphilis cases, is known as the cluster 
procedure. This procedure is composed of contact and cluster interviewing 
and involves three groups of people : contacts, cluster suspects, and cluster 
associates. 

Contact interviewing is especially designed to elicit from the infected 
patient information which will make it possible to find and bring to exami- 
nation that group of people with whom the patient was sexually intimate 
during the period of time in which the disease could have been acquired 
or spread (contacts) and an additional group the patient feels would 
benefit from an examination (cluster suspects). The patient may believe 



650 William W. Frye 

that a person would benefit from an examination for any of the following 
reasons: 

1. The person has or has had lesions similar to the patient's lesions 
or ones which are suggestive of syphilitic infection. When cluster suspects 
fitting these criteria are named by an infected patient, one out of every 
ten examined will be infected and in need of treatment. 

2. The person lives within or visits frequently the patient's household 
and/or is a sexual partner or friend of the patient's sexual partners. Cluster 
suspects so designated will be infected 3 per cent of the time (one out of 
every 33 examined). 

3. The person is a sexual partner or friend of a previously known 
syphilitic patient. Cluster suspects so designated will be infected 4 per cent 
of the time (one out of every 25 examined). 

Cluster interviewing is performed on noninfected contacts of early 
infectious syphilis during the course of the epidemiologic process and is an 
extension of the contact interview to include persons other than the 
original patient's contacts and cluster suspects. This type interview should 
be applied to noninfected contacts, not for the purpose of eliciting their 
sexual partners per se, but to take advantage of their knowledge about the 
extent of the disease in their immediate community and social groups, and 
particularly those known to have been treated recently for syphilitic 
infection (cluster associates). 

Associates obtained from cluster interviewing gave the following 
results : 

1 . Persons designated by the noninfected contact as having or having 
had lesions which are suggestive of syphilis will be infected slightly more 
than 3 per cent of the time (one out of every 30 examined). 

2. Persons designated by the noninfected contact as being sex partners 
or friends of a previously known syphilitic patient will be infected slightly 
less than 3 per cent of the time (one out of every 35 examined). 

It is apparent from these findings that infected patients and their 
noninfected contacts have a great deal of knowledge concerning their 
immediate community and/or socio-sexual group. Therefore, the eliciting 
of cluster suspects and cluster associates must be considered a necessary 
and integral part of effective epidemiology. 

The obvious problem that exists in the widespread application of 
epidemiology to early infectious syphilis is the failure of the private physi- 
cian to report all diagnosed cases. 

In 1962, the American Social Health Association, in cooperation with 
the American Medical Association, the American Osteopathic Association 
and the National Medical Association, conducted a mail survey of all 
practicing physicians to determine the number of venereal disease patients 
being treated by private physicians in a three-month period, April 1 
through June 30. 

Prior to the mail survey, information compiled from private physician 



Importance of Contact Investigation in Control of Syphilis 651 

morbidity reports to the state health departments indicated that the 
private physician was treating approximately one-third of the early infec- 
tious syphilis cases. However, the 131,245 replies to the Survey Question- 
naire (71.7 per cent of the physicians queried) indicated that the private 
physician was treating in excess of three-fourths of the early infectious 
syphilis cases and reporting only 11.3 per cent of these cases to state 
health departments. 

As Dr. Frye has so ably pointed out, syphilis will not be eradicated 
until epidemiology is applied vigorously to all known cases of early infec- 
tious syphilis. Therefore, an increased effort is being exerted, through 
individual private physician visitation, through work with national and 
local medical societies, and through articles appearing in professional 
publications, to encourage complete case reporting by private physicians. 



Late Benign Syphilis (Gumma) 



SIDNEY OLANSKY, M.D.* 



There has been a tendency on the part of many physicians to 
omit routine serologic testing for syphiUs (STS). Failure to perform these 
tests as part of the routine examination eliminates one of the most impor- 
tant ''suspicion arousers" in a disease where a high index of suspicion is 
essential. A reactive serologic test for syphilis immediately brings in the 
possibility of syphilis as an explanation for the signs and symptoms of the 
patient. Naturally, a reactive STS in itself does not make a diagnosis of 
syphilis, but it must be ruled out and the reactive STS must be explained. 
There is no substitute for a good history and physical examination in 
evaluating any patient, but this is especially true in a patient with a 
reactive serologic test for syphilis. 

For the past few years, early syphilis has been definitely increasing in 
incidence and we can expect soon to see a rise in late syphilis. In the past 
year, as a result of routine serologic testing for syphilis, we have been able 
to diagnose one case of paresis and two cases of gumma which would have 
been overlooked without the aroused suspicion created by the reactive 
serologic test for syphilis. In late benign syphilis we are observing a patient 
who has been previously sensitized to the Treponema 'pallidum. 

NATURAL HISTORY 

The earliest tertiary lesions seen clinically are those which occur 
following spontaneous healing of secondary syphilis or inadequately treated 
secondary syphilis. In the era of treatment with arsenic and bismuth these 
were considered relapses, and indeed many of them must have been, but 
with penicillin therapy most patients are treated adequately and these 
probably now represent reinfection in people previously sensitized to the 
Treponema pallidum. This type manifests as multiple and relatively non- 
destructive lesions and can be distinguished from secondary syphilis only 



Read at, Syphilis: A Symposium, Vanderbilt University School of Medicine, Nashville, 

Tennessee, May 17-18, 1963 
* Professor of Medicine (Dermatology), Emory University School of Medicine, Emory 

University Clinic, Atlanta, Georgia 

653 



654 



Sidney Olansky 



by the failure to obtain a positive darkfield examination. When these 
lesions heal they leave scars — a most unusual event following secondary 
syphilis. 

The more time that passes between the early disease and the appear- 
ance of benign tertiary lesions, the more solitary and destructive the 
lesions become. 



CLINICAL PICTURE 

The skin manifestations of benign tertiary syphilis may appear as 
nodular, nodulo-ulcerative or ulcerative lesions or as tumors breaking down 
to typical punched-out ulcers or gummas. The host response determines 
which of these types of lesions presents. With a lesser degree of sensitivity 
the lesions are more nodular, and with a greater degree of sensitivity they 
are more ulcerative. 





Figure 1. Benign late syphilis (nodular type) showing striking resemblance to 
tinea corporis. 




1 



Figure 2. Nodular syphilid 
resembling tinea corporis. (See 
also Plate III.) 



Late Benign Syphilis (Gumma) 



655 



Figure 3. Nodular ulcerative 
syphilid resembling tinea. (See 
also Plate III.) 




Figure 4. Stasis ulcer re- 
sembling gumma. (See also 
Plate III.) 



'"'■}.< 




The basic characteristics of late benign syphilis are as follows: 

1. The serologic tests for syphilis are reactive. 

2. Usually the lesions are solitary or few in number except in the 
so-called ' 'relapses." 

3. Asymmetrical distribution of the lesions is usual but by no means 
invariable. 

4. Induration is almost invariable. The lesions usually have '^feel." 

5. Indolence is characteristic and almost invariable. 

6. The lesions tend to be arciform or polycyclic. This feature is a 
very characteristic one and should arouse suspicion on morphologic grounds 
alone (Figs. 1, 2 and 3). 

7. The lesions are destructive although, at times, this feature may be 
quite minimal (Figs. 4, 5, 6 and 7). 

8. There is a tendency to partial healing without therapy, but spon- 
taneous complete healing is unusual. 

9. The scars are atrophic and noncontractile. 

10. There is persistent peripheral hyperpigmentation around the 
border of the lesion. 

11. The lesions respond quickly and dramatically to treatment with 
bismuth, penicillin or other antisyphilitic drugs. 



656 



Sidney Olansky 



Fig. 5 



■«! 




Fig. 6 
Figure 5. Ulcerative benign syphilis. The arcuate configuration is very char- 
acteristic. 

Figure 6. Ulcerative benign syphilis of the elbow. 




Figure 7. Gumma of the 
nipple. 



PLATE III 





Fig. 2 Nodular syphilid resembling Fig. 3. Nodular ulcerative syphilid 

tinea corporis. resembling tinea. 




4 




Fig. 4. Stasis ulcer resembling Fig. 9. Leprosy resembling nodular 

gumma. syphilid. 






Fig. 12. Nodular ulcerative syphilid 
of elbow (Case II). 



Fig. i;^. Positive STS and history of 
syphilis resembling gumma (Case IV). 



Late Benign Syphilis (Gumma) 

SEROLOGIC TESTS FOR SYPHILIS 



657 



The serologic tests for syphilis are always reactive in active benign 
tertiary syphilis and frequently in quite high titer. There are some reports 
in the literature of gumma with a nonreactive serologic test for syphilis, 
but careful analysis of these reports leads to the following conclusions: 

1. The diagnosis may be wrong. 

2. The result of serologic test for syphilis may be in error. This was 
especially true with the older serologic tests for syphilis which were low in 
sensitivity — for example, the old Wassermann test. 

3. The lesion may be the result of an old gumma — for example, 
perforation of the nasal septum or palate. In this instance, particularly in 
very late congenital syphilis, it is possible for the serologic test for syphilis 
to become negative if enough time elapses following the appearance and 
treatment of the lesion. This is similar to the nonreactive serologic test for 
syphilis observed in an old burned-out tabes dorsalis. 



DIFFERENTUL DUGNOSIS 

Tuberculosis of the Skin, Tuberculosis may resemble gumma clinically 
and pathologically since both are chronic granulomas. A patient with 
tuberculosis may also have latent syphilis. The causative organism of 
tuberculosis can usually be identified in tissue or on culture, which serves 
to differentiate tuberculosis from late benign syphilis. 

Sarcoidosis of the Skin. Clinically, this may resemble tuberculosis of 
the skin and also gumma but the histopathology of sarcoidosis is fairly 
characteristic. There is less tendency to destruction and these patients 
usually have nonreactive serologic tests for syphilis. A therapeutic test 
with antisyphilitic drugs may be necessary to distinguish sarcoidosis from 
benign tertiary syphilis, however (Fig. 8). 

Leprosy, The clinical lesions of leprosy may resemble syphilis, and 



Figure 8. Benign late syphilis 
(nodular type) resembling lupus 
vulgaris or sarcoidosis. 




658 



Sidney Olansky 




Figure 9. 
Figure 10. 



Fig. 9 Fig. 10 

Leprosy resembling nodular syphilid. (See also Plate III.) 
Late benign syphilis resembling discoid lupus erythematosus. 



many patients with leprosy have a reactive serologic test for syphihs which 
is a biologic false positive reaction. The areas of cutaneous anesthesia and 
the finding of Mycobacterium leprae in scrapings from the skin lesions 
usually can distinguish leprosy from late benign syphilis (Fig. 9). 

Sporotrichosis. Sporotrichosis may resemble gumma, although usually 
these nodules are more painful and inflammatory. A fungus culture reveal- 
ing Sporotrichum schenckii will differentiate it from gumma. 

Blastomycosis. This granulomatous lesion may resemble gumma, 
especially on the leg or on the face. Fungus cultures and direct mounts 
will reveal Blastomyces dermatitidis or yeastlike budding organisms which 
would confirm the diagnosis of blastomycosis. 

Actinomycosis. Actinomycosis may resemble gumma of the lymph 
nodes in the neck. The pathology and the demonstration of actinomyces 
hovis differentiates it from late benign syphilis. 

Psoriasis. Psoriasis may often resemble nodular or nodulo-ulcerative 
lesions. However, the patient with psoriasis usually has a nonreactive 
serologic test for syphilis and the pathology of psoriasis is entirely different 
from that of syphilis. 

Discoid Lupus Erythematosus of the Face. Clinically, discoid lupus 
erythematosus can be confused with late benign syphilis, but the pathology 
of lupus erythematosus is quite distinct from that of syphilis (Fig. 10). 

Tinea Corporis. Tinea corporis may have a striking resemblance to' 
nodular syphilis but a positive fungus culture and a potassium hydroxide 
preparation will distinguish it from that disease (Figs. 1 and 2). 

Factitial Eruptions. Particularly on the legs, factitial eruptions may 
be difficult to differentiate clinically from gumma. Usually, persons with 
these eruptions have nonreactive serologic tests for syphilis and the 



Late Benign Syphilis (Gumma) 

pathology is that of an acute ulcer rather than the chronic granulomas 
seen with late benign syphilis. 

Sickle Cell Ulcers. These must be distinguished from gummas of the 
leg. The diagnosis of sickle cell anemia in the patient would serve to 
establish the etiology. 

Epithelioma. Some epitheliomas, particularly those of the face, may 
be difficult to distinguish clinically from late benign syphilis. Biopsy of 
the epithelioma is characteristic and would rule out the diagnosis of late 
benign syphilis. However, an epithelioma may arise on a gumma or on an 
old healed gummatous scar. 

Persistent Erythema Multiforme. This disease may resemble nodular 
syphilis clinically. The serologic test for syphilis is usually nonreactive and 
the histopathology is quite distinct from that of late syphilis. 

Lymphoma. Cutaneous manifestations of lymphoma, particularly 
mycosis fungoides, may clinically resemble late benign syphilis. However, 
lymphoma usually is associated with considerable pruritus and the pathol- 
ogy is quite distinct from that of late benign syphilis. 

Granuloma Inguinale. Granuloma inguinale may spread in arcuate 
fashion and may superficially resemble late syphilis. Frequently these 
patients also have latent syphilis and a considerable number may well 
have a reactive serologic test for syphilis. In granuloma inguinale, Donovan 
bodies can be demonstrated directly from the lesion and the histopathology 
is quite different from that of syphilis. 

Pyoderma Gangrenosum. Pyoderma gangrenosum involving the lower 
extremities may resemble gumma but is usually much more acute than 
gummatous ulcers and is frequently associated with ulcerative colitis and 
with generalized illness not usually seen with late benign syphilis. These 
patients usually do not have a reactive serologic test for syphilis and the 
pathology of these lesions is an acute vasculitis. 

Granuloma Annulare. This disease may resemble late benign syphilis 
since it is very asymptomatic and has the morphology of late nodular 
syphilis. In this situation, the serologic test for syphilis is usually nonreac- 
tive and the pathology is distinctive, showing necrobiosis rather than the 
chronic granuloma seen in late syphilis. 

Bromoderma. These vegetative lesions may be quite confusing on the 
lower extremities. Usually these patients do not have a reactive serologic 
test for syphilis and the blood bromine level is high. 

Leukoplakia of the Mouth. True precancerous leukoplakia has a dis- 
tinctive pathologic picture whereas so-called leukoplakia associated with 
late syphilis is quite different. The latter is responsive to antisyphilitic 
drugs whereas true leukoplakia is not. 

Lichen Planus. Lichen planus may present with annular lesions 
particularly over the penis and may be confused with late nodular syphilis. 
Lichen planus is, however, frequently pruritic and has a very distinct 
histopathology. Lichen planus in the mouth may be confused with leuko- 



660 Sidney Olansky 

plakia. A biopsy serves to distinguish it both from leukoplakia and late 
syphilis. 



DIAGNOSIS 

There is no single test such as the darkfield examination which can 
unequivocally make the diagnosis of late benign tertiary syphilis. It is 
suspected when the serologic test for syphilis is reactive and the lesions 
present are compatible with a diagnosis of benign tertiary syphilis. The 
histopathology is merely suggestive and cannot be easily distinguished 
from other chronic granulomas, such as tuberculosis. Often the diagnosis 
rests on the therapeutic test. Benign tertiary syphilis will respond quickly 
and dramatically to bismuth, penicillin or other antibiotics such as erythro- 
mycin, tetracyclines and chloramphenicol, whereas the diseases which can 
be confused with syphilis usually will not. 

Gumma may appear at any time from one to ten years after initial 
infection. It should be remembered that all lesions associated with latent 
syphilis are not gummas. The therapeutic test generally distinguishes the 
late lesions of syphilis from other conditions that may coexist with latent 
syphilis. 



THEORIES OF GUMMA FORMATION 

Hudson and others have proposed a unitarian etiology for all the 
treponematoses. The morphology of the organisms, the serologic reactions, 
animal studies and even the clinical expressions are similar, if not identical, 
in all of the treponematoses (yaws, bejel, endemic syphilis, pinta, etc.). If 
one can accept Hudson's view, and I do, the late benign lesions of syphilis 
can best be observed in nonvenereal or endemic syphilis. 

In endemic syphilis large numbers of the population are infected, 
among them many children. If the epidemic persists, these children and 
others have an adequate opportunity to become re-exposed to fresh 
organisms after they have been treated or when the disease subsides. Those 
who have become sensitized by virtue of the previous infection usually 
have gummas at the site of re-exposure. When these epidemics are con- 
trolled by adequate treatment of all known cases, benign tertiary syphilis 
virtually disappears. Where tertiary syphilis is frequent, there are large 
reservoirs of Treponema pallidum as shown by the occurrence of numerous 
fresh early cases. Grin has written extensively on the incidence of gumma 
in endemic syphilis. He reports that in some households benign tertiary 
syphilis appears at the same time or shortly after other members of the 
family have fresh infections. He reports a family of 15 people where the 
eldest son was treated 18 years previously. A fresh infection developed in 



Late Benign Syphilis (Gumma) 661 

three members and some months later in seven other members of the 
family. At this time, the previously treated eldest son developed a gumma. 
He concludes that the pathogenesis of tertiary syphilis seems to be repeated 
exposure in already sensitized people. 

Grin feels that benign tertiary syphilis develops for two reasons: 
(1) reactivation of residual Treponema pallidum in sensitized individuals 
who are inadequately treated, or (2) exogenous re-exposure in sensitized 
persons who have been adequately treated. There is some experimental 
support for each of these concepts. 

In the Sing Sing study of 1952, 62 volunteers were inoculated with the 
Nichols strain of Treponema pallidum. That this strain was an active one 
was demonstrated by the fact that eight controls who had not previously 
had syphilis were all infected, with the development of darkfield-positive 
lesions at the site of inoculation, and those who were not treated at this 
point developed lesions of secondary syphilis. Among the volunteers were 
26 who had been adequately treated previously, representing late latent 
syphilitics. Ten of the 26 men in this category developed infection as a 
result of challenge and one of the ten developed a gumma at the site of 
inoculation. There was also a group of five late congenital syphilitics who 
had been adequately treated, and one of these developed a gumma at the 
site of challenge. The serologic response to the challenge and to subsequent 
treatment was quite similar in the patients who developed the gummas 
to that in all the other infected patients in the same categories. 

From this observation we can conclude that, under the circumstances 
of this study, those who developed gummas at the site of challenge were 
infected and that all of the spirochetes were not destroyed locally. This 
provides evidence, I believe, that exogenous exposure may produce gumma 
at the site of introduction of Treponema pallidum. This leads to the further 
conclusion that some patients who have gumma may have been exposed 
to and infected by individuals with early syphilis. This sequence has been 
borne out clinically. Since the Sing Sing study was completed, epidemiology 
on patients with gumma has frequently led to the finding of early lesions 
in their sexual contacts. This was particularly true if the gumma was in 
the anogenital region. The Sing Sing study therefore would support Grin 
as regards exogenous exposure in a sensitized individual as one of the 
explanations of gumma. 

Recently, Collart et al. conducted some studies which may have some 
bearing on the understanding of gummas. They found Treponema pallidum 
in the inguinal lymph nodes of nine patients who had had syphilis which 
had been adequately treated several years previously. They demonstrated 
these treponemes by silver staining techniques. In four cases, part of the 
lymph node was inoculated into rabbits, and in three, Treponema pallidum 
could be found in the lesions which developed at these sites. In these 
rabbits, the Treponema Pallidum Immobilization Test did not become 
positive and the rabbit was technically not infected. Collart and his 



662 Sidney Olansky 




Figure 11. Ulcerative benign 
syphilis of the leg (Case I) 



co-workers inferred from this that the Treponema pallidum retained its 
morphology but lost its virulence. In another study, they inoculated 
rabbits with Treponema pallidum and after two years treated them with 
benzathine penicillin (Bicillin). One year later lymph nodes were removed 
from these rabbits, and smears revealed Treponema pallidum by silver 
staining techniques. Transfer of these nodes to fresh rabbits, however, did 
not produce infection. Cortisone was given to one of these treated latent 
rabbits and this rabbit developed typical late syphilis. Collart thought 
that the cortisone upset the immunity sufficiently to allow the spirochete 
to again become virulent and antigenic. This work would tend to support 
Grin's feeling about endogenous Treponema pallidum and their part in the 
production of gummas in the inadequately treated individual. 

If a high index of suspicion is necessary to diagnose early syphilis, it 
is perhaps even more so in late syphilis. The following case reports illustrate 
this fact. 

Case I. J.V., a 70 year old male Negro, had been attending a varicose vein 
clinic for the treatment of unilateral ulcers of the leg of approximately 18 months' 
duration. Unna's boots had been apphed with great regularity with no real effect 
on the lesions. The lesions continued to develop in one area as they healed in another. 
They were asymptomatic and when they healed showed noncontractile scars and 
hyperpigmentation at the borders (Fig. 11). Since the patient did not respond to 
varicose ulcer management, it was felt that surgical intervention was necessary and 
at this time a serologic test for syphiUs was made and found to be reactive. He was 
then referred to the Rapid Treatment Center for the treatment of his blood so that 
surgery could be performed. Even with the reactive serologic test for syphilis, the 
possibility of gumma was not considered. The patient was treated with chloram- 
phenicol which was being used experimentally at that time. The lesions healed 
completely in less than 2 weeks and he remained well for approximately 6 years 
after therapy, when he was lost to follow-up. 

Case II. J.C., a 65 year old Negro, was admitted to the hospital with a 
chronic hypertrophic ulcerative lesion over the elbow. He was considered to have 
a deep fungus infection. Many attempts to culture the organisms of blastomycosis, 
sporotrichosis, and other deep fungi were made without success. He was skin tested 
to all of the known fungal extracts with negative results. The possibiUty of tuber- 



Late Benign Syphilis (Gumma) 



663 



culosis was considered and ruled out as were the other chronic granulomas, with 
the exception of syphilis (Fig. 12). When I was called to see the patient after all 
these diagnostic studies had been made, it was apparent that the only test not 
previously done was the serologic test for syphilis. This proved to be highly re- 
active. PenciUin therapy was administered and produced rapid healing of an ulcer 
which had been present for approximately 8 months. The lesion was a gumma. 

Case III. A 12 year old Negro child was seen with enlarged, nontender lymph 
nodes in the neck which were draining what seemed to be rather thin pus. Because 
she was Negro and because of the location of the nodes, tuberculosis was considered 
to be the most Ukely diagnosis. However, the skin test for tuberculosis was negative, 
x-ray of the chest and bones revealed no evidence of tuberculosis, cultures for 
actinomycosis were negative and ultimately the serologic test for syphilis was 
performed and was strongly reactive. History at this time revealed that this child 
had late congenital syphilis. Bismuth therapy was administered and the lesions 
were completely healed within a period of 3 weeks. The diagnosis was gumma of the 
lymph nodes of the neck. 

Occasionally, what seems to be syphilis turns out not to be, as illus- 
trated by the following case. 

Case IV. M.J. was a 60 year old white man with 3 draining sinuses in the 
neck just above the right clavicle (Fig. 13). The patient was known to have had 



Figure 12. Nebular ulcerative 
syphilid of elbow (Case II). (See 
also Plate III.) 



Figure 13. Positive STS and 
history of syphilis resembling 
gumma (Case IV). (See also 
Plate III.) 




664 Sidney Olansky 




Figure 14. Benign late syphilis 
(nodular type) (Case V). 



syphilis in the past, had been adequately treated and his serologic test for syphilis 
was reactive in a low titer. Biopsy from one of the sinuses revealed basal cell 
carcinoma which responded dramatically to x-ray treatment. It should be mentioned 
that he had been given peniciUin previously on the supposition that these were late 
syphihs lesions. 

Case V. C.S., a 45 year old white man, was seen in a dermatology cUnic with 
the chief complaint of a persistent eruption previously diagnosed as a fungus infec- 
tion of the palms of the hands and forearms of 18 months' duration. Physical exam- 
ination revealed a shghtly nodular, hyperpigmented eruption with slight tendency 
to healing. The eruption appeared in the form of circles and segments of circles and 
had extended very slowly over the period of 18 months to involve both palms and 
forearms almost to the antecubital areas (Fig. 14). The lesions were completely 
asymptomatic. The patient's description was, "I would like to get rid of this rash 
because when I get into a bathing suit or wear short sleeves, it looks bad. People 
might think I have a contagious disease." A routine serologic test for syphilis was 
reactive in high titer. Penicillin therapy melted the lesions away. The diagnosis was, 
of course, late benign syphilis of the nodular type. 

These case histories illustrate only partially the wide range of clinical 
expressions possible in late benign syphilis which are visible to the naked 
eye. They support the need for a high index of suspicion and for the 
performance of routine serologic tests for syphilis in any good medical 
work-up. All of these patients had reactive serologic tests for syphilis but 
four of them had lesions of late syphilis and one did not. This emphasizes 
the need for evaluating the laboratory test results in terms of the whole 
patient. A firm diagnosis of late benign syphilis, if correct, is a very desirable 
diagnosis to make because therapy for this is usually much simpler, safer 
and surer than are the therapies available for most of the conditions from 
which it must be differentiated. 

No mention has been made, so far, of the late benign lesions which 
arc not visible to the naked eye, i.e., visceral lesions. Late benign lesions 
of syphilis have been reported in practically every organ. Lack of space 
makes it impossible to go into detail about the diagnostic features of each 



Late Benign Syphilis (Gumma) 665 

of these. However, the diagnostic principles are exactly the same whether 
the lesions are directly or indirectly visible. The reactive serologic tests for 
syphilis should alert the clinician to the possibility that syphilis is respon- 
sible for the signs and symptoms. If the possibility of visceral benign 
tertiary syphilis cannot be eliminated, a therapeutic test with bismuth, 
penicillin, erythromycin, tetracyclines or chloramphenicol will almost invar- 
iably provide the evidence needed to prove or disprove the diagnosis of 
late benign syphilis. 



CONCLUSIONS 

The diagnosis of late benign syphilis is dependent upon (1) routine 
serologic tests for syphilis, (2) a high index of suspicion, (3) good medical 
principles, and (4) a therapeutic test with antisyphilitic drugs. If all the 
above factors are properly considered, the ability to cure some patients 
with simple, safe therapy who might otherwise have been considered 
incurable or doomed will be rewarding indeed. 



GENERAL REFERENCES 

1. Stokes, J. H., Beerman, H. and Ingraham, N. R.: Modern Clinical Syphilology. 

3rd Ed. Philadelphia, W. B. Saunders Co., 1944. 

2. Hudson, E. H.: Non-venereal Syphilis. Baltimore, Williams & Wilkins, 1958. 

3. Grin, G. I.: Endemic Treponematosis. Tr. St. John's Hospital Dermatological 

Society, Vol. 48, No. 1, 1962. 

4. Turner, T. B. and Hollander, D. H.: Biology of the Treponematoses. World Health 

Organization, Geneva, 1957. 

5. Magnuson, H. J., Thomas, E. W., Olansky, S., Kaplan, B. I., DeMello, L. and 

Cutler, J. C: Inoculation Syphilis in Human Volunteers. Medicine 35 (1): Feb., 
1956. 

6. Collart, P., Borel, L. J. and Durel, P.: Etude de Taction de la penicillini dans la 

syphilis tardine. Persistace du triponime pale apres tratement (Parts I and II). 
Ann. de L'Institut. Pasteur, Vol. 102, June, 1962. 

7. Ibid. (Part III), Vol. 103, Dec, 1962. 

8. Kampmeier, R. H.: Essentials of Syphilology. Philadelphia, J. B. Lippincott Co., 

1944. 

9. Grin, E. I.: Epidemiology and Control of Endemic Syphilis. World Health Organiza- 

tion Monograph Series, Geneva, 1953. 

Emory University Clinic 
Atlanta, Georgia 



The Late Manifestations of Syphilis: 
Skeletal, Visceral and 
Cardiovascular 

R. H. KAMPMEIER, M.D.* 



Beyond the early years of the syphihtic infection with its 
infectious lesions — the chancre, the condyloma latum, and mucous patches 
— and the evidences of recurrent spirochetemia as mucocutaneous relapse, 
neurorelapse, infection of the infant in utero, and the occasional transmis- 
sion of syphilis by blood transfusion, the clinician turns his attention from 
these public health aspects of the disease, to the morbidity and mortality 
of its late manifestations. 

The immunopathologic progress of the syphilitic infection from its 
inception through a subclinical course of latency to end in spontaneous 
''cure," or of activity to cause death three decades or more after infection 
offers a series of confusing and unexplained events difficult of correlation. 
The primary or secondary lesions are characterized by a remarkable 
infiltrate of plasma cells, lymphocytes and fibroblasts, especially about the 
small vessels. Numerous treponemes and the same inflammatory infiltrate 
are found about the capillaries. The secondary lesion tends to be a pro- 
liferative process and focal lesions are found in the corium separate from 
the areas involved in the rash. 

The importance of calling attention to the immunopathologic processes 
of early syphilis is their bearing upon the later manifestations of the disease. 
Recurrent crops of papules appearing simultaneously with healing of like 
lesions elsewhere may be characteristic of clinical relapse in the early years 
of the infection. This suggests that immunity is not humoral, but rather a 
specific "tissue immunity," with an element of a hypersensitivity reaction 
or response to the treponeme or a product from it. This poses unanswered 
questions as to degrees of tissue immunity varying from host to host. It 
asks for answers to a number of questions: Why does the treponeme 



Read in part at the Symposium on Venereal Disease, The 112th Annual Meeting of the 
American Medical Association, June 20, 1963, Atlantic City, New Jersey 

* Professor of Medicine, Emeritus, and Director of Continuing Education, Vanderbilt 
University School of Medicine, Nashville, Tennessee 

667 



668 R. H. Kampmeier 




Figure 1. Darkfield-positive lesion 
following trauma. The fourth infectious 
relapse (darkfield-positive in each) in 3 
years since the primary penile lesion. 
(Total treatment included 34,200,000 
units of penicillin, 15 injections of 
Mapharsen and 9 of bismuth. Seronega- 
tivity attained after 4 years of positive 
tests.) (Courtesy South. M. J. 46: 226, 
1953.1) 



become established in the cerebrum of certain hosts during the spiroche- 
temia of the early years of the infection gradually to cause the changes to 
be recognized clinically after two decades as paresis, having in the mean- 
time carried the sign of active involvement in the spinal fluid? On the 
other hand, why, in the majority of patients, has the treponeme not gained 
a foothold in the cerebrum at the time of spirochetemia? Why has the 
treponeme invaded the central nervous system to leave its mark as tabes 
dorsalis and then ''burn out" without treatment? Or, why, in certain of 
the hosts, has the treponeme been attracted to a continuance of recurrent 
inflammation and healing in the aortic wall and, why, in others, has this 
not occurred though all infected have been exposed to spirochetemia? Or, 
why, in contrast to alternating inflammation and fibroblastic proliferation 
in some hosts, does the gumma appear in others? This is the lesion in 
which, presumably, a very few organisms (impossible of demonstration by 
darkfield examination but proven at times by animal inoculation) incite a 
massive localized inflammatory response with necrosis and giant cell forma- 
tion, suggestive of reaction in a hypersensitive tissue. What factors account 
for this sudden response to a presumed focal syphilitic inflammation 10 or 
20 years, or more, after the spirochetemia of the early years of the disease? 
That this represents a tissue response characteristic of only certain hosts 
is highly probable because of the frequency with which multiple gummas 
appear, even simultaneously, in the same individual. Whether biochemical 
or other immunologic factors play a role in the sudden exacerbation which 
is the gumma is unknown. Repeatedly, however, trauma seems to be an 
inciting factor in the development of syphilitic periostitis or osteitis, 
reminiscent of its role in acute pyogenic osteomyelitis. This recalls the 



The Late Manifestations of Syphilis 669 

occasional instances of an infiltrative and ulcerative response to trauma 
during a time of spirochetemia, as shown in Figure 1.^ 

In considering the late manifestations of syphilis, an understanding of 
the natural course of the untreated infection is essential. If Figure 2 is 
accepted as portraying the biologic course of infection, it is apparent that, 
except for rare instances, the late manifestations of the disease appear 
above the clinical horizon only after some eight to ten years following 
infection to end with death either as the result of syphilitic or other disease. 
Rosahn,^ in an intensive study of necropsy material at the Yale University 
School of Medicine to establish acceptable criteria for the pathologic 
diagnosis of syphilitic disease in contrast to those of Warthin, has offered 
figures which are remarkably similar to the Oslo figures appearing in 
Figure 2 based on Boeck's clinical diagnoses.* (See paper by E. Gurney 
Clark in this volume.) His material came from 380 syphilitic persons of 
whom 198 or 52 per cent had received no antisyphilitic treatment. Among 
these, 77 (39.9 per cent) showed anatomic lesions of syphilis, though only 
23.2 per cent of the group died primarily of syphilis. The 106 lesions found 
in this untreated group were the following: 88 (83 per cent) in the cardio- 
vascular system, 8 (7.6 per cent) in the central nervous system, and ten 
(9.4 per cent) had gummatous lesions of various organs and cirrhosis of 
the liver. The remaining 121 patients (61.1 per cent) of the 380 syphilitic 
persons showed no anatomic lesion of syphilis, though in 80 (40.4 per cent) 
the serologic test was positive during the last hospitalization, and in 35 
(17.7 per cent) it was negative. 



UNTREATED ACQUIRED SYPHILIS 
The Course of Disease and Blood Tests 

PRIMARY ^___ COURSE of untreated disease 

' SECONDARY ' incidence - Oslo study) 

1 POSITIVE BLOOD 

I „^7^tX,- POSITIVE, DOUBTFUL OR NEGATIVE 



CLINICAL 
HORIZON 



YEARS 5 10 15 20 25 30 

Figure 2. The natural history of untreated acquired syphilis. (Modified from 
original, courtesy South. M. J. 26: 18, 1933.^ Incidence of clinical disease from Clark 
and Danbolt,2 J. Chron. Dis. 2: 311, 1955.) 

* Rosahn accepted, in general, the criteria proposed by Nickel: "Definite anatomic 
changes of syphilis of the central nervous system, vascular tree, bone, and paren- 
chymatous organs including the liver." (Nickel, H.: Statistiche Untersuchungen iiber 
die Haufigkeit der Lues am Obductions material. Klin. Wchnschr. 15: 121, 1936.) 



670 



R. H. Kampmeier 



INCIDENCE OF LATE SYPHILIS 

VANDERBILT UNIVERSITY HOSPITAL 




160 leo 200 220 
NUMBER OF CASES 



*CONGENITAL-(rHOSE OVER AGE IS YEARSi 



Figure 3. The decrease in the incidence of late syphilis in the Vanderbilt Uni- 
versity Hospital Syphilis Clinic. (The experience of the first 15 years could not be 
broken down by 5-year periods, therefore a 5-year average for this period is used for 
comparative purposes.) (Courtesy South. M. J. 46: 226, 1953.0 



The succeeding discussion will include the late benign manifestations 
of syphilis exclusive of involvement of the skin, which is the subject of 
Dr. Olansky's presentation in this volume. Of the generally more serious 
late manifestations, attention will be directed only to aortitis and its 
complications, since Dr. Evan Thomas describes so well elsewhere in these 
pages the serious results of the invasion by treponemes of the central 
nervous system. 

Late manifestations became much less frequent in the years following 
intensive case finding, which was part of the epidemiologic control of 
syphilis that began in 1937, not only nationally, but also in the community 
related to Vanderbilt University Hospital. In the Syphilis Clinic established 
in this hospital in 1925, and in which an intensive program of case finding 
and treatment was begun in 1937, the fall-off in the late evidences of the 
disease is well shown in Figure 3.* 

One gains the impression — and it is only an impression — that the 
incidence of late benign lesions became much less frequent than did the 
cardiovascular ones. Whether this might be the result of healing of lesions 

* These figures represent the incidence of disease in which the diagnosis was made 
on ambulant clinic patients and does not include diagnoses made on ward patients. 
Unfortunately figures subsequent to 1952 cannot be included, since with the discon- 
tinuance of the Syphilis Clinic that year the syphilitic patients were absorbed into the 
general medical and/or specialty clinics. Thereafter syphilitic disease was often either 
not diagnosed and recorded or, if so, did not represent the critical diagnoses made in the 
former Syphilis Clinic at a history meeting and which included the consensus of thjee or 
four clinicians experienced in the disease. 



The Late Manifestations of Syphilis 671 

of the hypersensitivity type (the gumma) by incidental treatment with 
peniciUin given for pneumonia, ''colds" or other reason, remains one of 
speculation. (The healed hepatic gumma, for example, leaves no clinical 
mark.) On the other hand, a similar effect of penicillin upon aortic lesions, 
if followed by the therapeutic paradox of scar and deformity of the aortic 
valves or the aortic ring and resultant regurgitation, would not register a 
comparable decrease in late disease. 



LATE BENIGN SYPHILIS* 

Historical Note. Adherents of the belief that syphiUs was of American origin 
cite the changes in pre-Columbian bones of Amicrican a! origine^ as evidence of os- 
seous syphilis. Similarly those who believe that the treponematoses were indigenous 
to the Eastern Hemisphere before the discovery of America point to the confusion 
between leprosy and syphilis in the Middle Ages and cite examples of bony changes 
in Europe, antedating 1492, thought then to be leprous. Then there are the interest- 
ing references to the efficacy of the Saracen's ointment (mercury) which the Cru- 
saders (llth-14th centuries) brought back to Europe from the Near East for the 
treatment of leprosy! In any event, the first medical descriptions of the late mani- 
festations of syphiUs by DeVigo — of the bone, iritis, and nasal ulcerations — 
appeared in 1514. It is remarkable that these should be recognized only 22 years 
after the discovery of America. In the following century appeared descriptions of 
visceral syphilis. The truly scientific analyses and recognition of these lesions were 
contributed by Wilks and by Virchow in the nineteenth century. 

Pathology 

It was indicated above that late benign manifestations may represent 
a proliferative reaction in which, though clinically the patient may appear 
to be in the stage of latency, there is a chronically progressing inflammatory 
reaction, often with miliary gummas, replaced by a fibrosing process. This 

* It should be obvious that no extensive review of the literature has been attempted 
in this paper. If bibliographic references seem outdated, it should be recalled that the 
accumulated clinical knowledge about syphilis has long been well known and that the 
statistical evaluations pretty much reached their completion between 1930 and World 
War II. Retrospective studies were begun about a quarter of a century after the dis- 
covery of the T. pallidum and the first description by Wassermann of a test for the dis- 
ease. The chiefs of the Syphilis Clinics of the University of Pennsylvania, the Mayo 
Clinic, the University of Michigan, Western Reserve University and Johns Hopkins 
University and representatives of the U.S. Public Health Service composed the Cooper- 
ative Clinical Group. In a series of papers beginning in 1932 they brought order out of 
confusion and laid the foundation for modern syphilology. These studies provided the 
bench mark for the rapid and satisfactory cooperative evaluation of intensive arseno- 
therapy in the late 30' s and early 40' s, and then for similar studies upon the efficacy of 
penicillin therapy between 1943 and 1947. 

Major contributions in the past 15 years have been in the areas of the newer 
therapy, development of specific diagnostic tests, and the sociologic facets playing a 
role in epidemiology in the disease. References will be made to what I consider the 
greatest contributions in the clinicopathologic field since the War, the autopsy studies by 
Rosahn^ and the statistical re-evaluations of the Oslo cases on the natural history of 
untreated syphilis by Clark and Danbolt^ (as reported in this volume). 



672 R. H. Kampmeier 

Table 1. Distribution oj Late Benign Lesions as to Site and Race 

SITE NEGRO WHITE 



Skeletal (all types) 123 55 

Skin 124 47 

Upper respirator ^ tract (nose, throat, larynx) 50 19 

Mucous membrane (mouth) 41 19 

Eye (all types) 43 11 

Visceral (liver, stomach, etc.) 23 14 

Lower respiratory tract (?) 2 2 

Mediastinum (?) 3 1 

Lymph nodes 7 — 

Genital tract (female) 4 — 

Penis 3 2 

Testis 3 1 

Skeletal muscle 3 1 

Totals 429 172 



may, depending upon the site and organ involved, leave such scarring as 
ultimately to end in severe disturbance of function of the affected tissues. 
Or, the gumma may present a truly destructive lesion, an explosive tissue 
reaction to a few organisms resulting in a granuloma or tumor which may 
vary from microscopic size to 5 centimeters or more in diameter. The 
larger gummas may undergo central necrosis and break through their wall 
to drain by one or more sinuses. Commonly such a destructive lesion is 
followed by extensive and disfiguring scar. 

Incidence and Distribution 

Precocious tertiarism may occur toward the end of the secondary stage 
of syphilis when the skin lesions, though actually representing relapse as 
shown by a positive darkfield examination, may begin to take on some of 
the characteristics of the late syphilid, with its serpiginous progressing 
border.* Usually, however, the granulomatous lesions show themselves 
after some eight or ten years to 20 or 25 years, and less commonly 35 or 
more years, after infection. Table 1 gives the incidence of clinically diag- 
nosed late benign lesions in 6259 patients admitted to the Vanderbilt 
University Hospital Syphilis Clinic, from its opening in 1925 to 1943. 
There were 601 instances of late benign syphilis in these patients. It must 
be re-emphasized that in many patients gummatous lesions are multiple; 
the table lists the lesions by the anatomic structures involved. Negroes 
made up 67 per cent of admissions to the Syphilis Clinic; 71 per cent of 
the late benign lesions appeared in this race. (Patients given the diagnosis 
of late syphilis on the wards of Vanderbilt University Hospital are not 
included in this table.) 

From the table it will be seen that any tissue or anatomic structure 

* Such lesions were not uncommon in patients who were "treatment-resistant" 
because of irregularity in treatment under arsenotherapy." 



The Late Manifestations of Syphilis 673 

may be the site of late lesions. Attention is directed particularly to the 
identical frequency of late disease in the skeletal system and of the skin. 
The upper respiratory tract, including the mouth, nose, throat and larynx, 
also is commonly involved. Of viscera the liver is most frequently affected. 
(Patients with this lesion are more likely to be admitted directly to the 
ward service rather than to an outpatient service.) The remainder of the 
late benign lesions represent rather rare clinical entities. 

Syphilis of the Skeletal System 

Since the late cutaneous syphilids have been considered by Dr. Olansky, 
attention will be directed first to disease of the skeletal system which was 
involved as often as the skin in our clinic. All bones of the skeletal system 
have been known to be affected by syphilitic disease. 

Table 2 presents a radiologic analysis of 67 cases of skeletal syphilis 
at Vanderbilt University Hospital in which the films were still a-v^ailable 
and adequate for study. ^ Our study excluded instances of bony involvement 
in prenatal or in early acquired syphilis, nor did it include cases of involve- 
ment of the nasal or palatine bones, or the neuro-arthropathies (Charcot 
joint). In the survey of 67 patients, 117 bones presented radiographic 
evidence of disease. This emphasizes the common multiplicity of late 
lesions in the same patient. (Without a doubt, had the whole skeletal 
system been examined radiographically in these 67 patients, many more 
lesions would have been recorded.) From a radiologic viewpoint, it seems 
probable that the pathologic changes begin usually as periosteal inflamma- 
tion or gummatous alteration with secondary changes in the adjacent bone 
as osteitis or osteomyelitis. From the radiologist's viewpoint, the lesions 
may be placed in three categories. (1) Periostitis is characterized by 
periosteal thickening and localized increased density similar to cortical 
bone, often as laminated layers or as a diffuse thickening, which may or 
may not be accompanied by destruction of bone (Fig. 4). (2) Gummatous 
osteitis presents as a destructive or osteomyelitic lesion associated with 
periosteal and/or osteal changes; there is a varying degree of sclerosis in 
the neighboring bone (Figs. 5, 6 and 7). (3) Sclerosing osteitis, in which a 

Table 2. Bones Showing Radiographic Evidence of Syphilis in 67 Patients^ 

Tibia 34 Mandible 2 

Clavicle 17 Facial bone." 

Skull 15 Sternum 

Fibula 15 Spine 

Femur 8 Radius 

Humerus 5 Metacarpal 

Rib 4 Metatarsal 

Ulna 3 Phalanx 

Scapula 3 Patella 

Malar bone 2 Ischium 



674 



R. H. Kampmeier 




Fig. 4 Fig. 5 

Figure 4. Periostitis without destruction. There is localized cortical thickening 
due to periosteal new bone formation with an undulating edge. (Courtesy South. M. J. 
36: 556, 1943.^) 

Figure 5. Gummatous destruction in both tibias without periosteal reaction; 
gummas with periosteal reaction involve the fibulas. (Courtesy South. M. J. 36: 556, 
1943.6) 



gumma may be small or obscure, represents a lesion in which the bone 
shows increased density and is usually accompanied by periosteal change 
(Fig. 8). The 117 lesions of bone were distributed among these three 
groups as gummatous osteitis in 73, periostitis in 28 and sclerosing osteitis 
in 16. 

As in all clinical diseases having pathologic changes subject to roent- 
genologic analysis, there will be a number of patients in whom the radio- 
graphic examination is negative. This is not surprising if one recognizes, 
for example, that sclerosing change in bone must reach the stage which 
can be shown upon the x-ray film. By contrast, however, it is equally 
obvious that periosteal reaction insufficient to cast a shadow may yet 
produce pain, tenderness, and changes in the overlying skin and respond 
rapidly to antisyphilitic treatment. Therefore an analysis of symptoms of 
skeletal involvement was made in 106 patients in whom the clinical 
diagnosis of late osseous syphilis was made.^ Among these an x-ray diag- 
nosis of gummatous osteitis was made in 36, of periostitis in ten, and of 
condensing osteitis in eight cases, or radiographic confirmation of the 



The Late Manifestations of Syphilis 

Table 3. Symptoms and Signs in 106 Cases oj Syphilis of Bone^ 



675 





NUMBER 




NUMBER 


SYMPTOMS 




SIGNS 






OF CASES 




OF CASES 


Pain 


. .... 79 


Tenderness 


80 


Swelling 


56 


Swelling 


55 


Nocturnal pain 


42 


Multiple sites 


53 


Bony tumor 


31 


Tumor 


48 


Stiffness 


26 


Limited motion 


22 


Tenderness 


20 


Redness 


15 


Trauma 


17 


Heat 


13 


Local heat (increased). . 


11 


Sinus 


8 


Redness 


.... 7 


Ulcer 


4 


Immobility 


.... 3 






Draining sinuses 


.... 13 







clinical diagnosis in 54 patients for a total of 72 lesions. In the 106 cases 
having a clinical diagnosis of skeletal syphilis, x-ray examinations were 
either not done or reported as negative in 52 cases, for 61 suspected lesions. 
The symptoms of the 106 patients with the clinical diagnosis of skeletal 
syphilis are listed in Table 3. The multiplicity of focal involvement in late 
syphilis is again well illustrated in these 106 patients since, in addition to 
multiple bone lesions, one-fifth had other diagnoses of late disease. These 




Figure 6. Gummatous osteitis as multiple destructive lesions. (Coincidental with 
gummatous hepatitis as shown in Figure 15.) 



676 



R. H. Kampmeier 




periosteal thickening. 



Fig. 7 Fig. 8 

Figure 7. Gumma. A destructive cystlike lesion with 
(Courtesy South. M. J. 36: 556, 1943.^) 

Figure 8. Sclerosing osteitis here shows wavy outlines of dense sclerotic bone. 
(Courtesy South. M. J. 36: 556, 1943.^) 



included tertiary involvement of the skin in 11, cardiovascular syphilis in 
five, neurosyphilis in five, syphilis of the larynx in one and of the testicle 
in one. In 40 of these patients in whom spinal fluid examination had been 
done, 11 were found to be seropositive. 

Symptomatology. Symptoms of skeletal syphilis result from inflam- 
mation of structures permitting only limited expansion. The periosteum is 
so intimately applied to bone that inflammation must cause severe pain; 
inflammation in the haversian canals or of the endosteum certainly adds 
to the pain. For similar reasons the major findings are exquisite tenderness 
over the involved areas and swelling of tissues overlying the affected 
periosteum, at times presenting true tumefaction and, not infrequently, 
redness and warmth of the skin of the area. Weight loss not infrequently 
accompanies more chronic bony involvement. A prompt response to anti- 
syphilitic treatment indicates the specific nature of the lesion.* 

Perichondritis. Comments made upon syphilitic periostitis can be 
applied to the perichondrium. Syphilis of cartilaginous structures, because 
of the greater vulnerability of this softer tissue, is likely to result in greater 
destruction. This is well shown in the occasional instance of involvement 

* This statement is based on past experience with medication specific for syphilis 
only. The relief of an inflammatory process by penicillin does not have the certain 
connotation as does the resolution of such a process by arsenic and /or bismuth. These 
drugs offer a diagnosis by therapeutic trial when the differential diagnosis involves other 
granulomatous disease of bone, such as tuberculosis, or even bone tumor. 



The Late Manifestations of Syphilis 



677 



of the perichondrium of the cartilaginous nasal septum, the external ear, 
or of the costal cartilage (Fig. 9). 

Differential diagnoses of skeletal syphilis will not be considered in 
detail since it might be carried too far afield. It should be recognized, 
however, that syphilis of bone must be differentiated from any other 
granulomatous disease, of which tuberculosis is the most frequent, as well 
as from chronic pyogenic osteomyelitis. Osteogenic tumors, primary and 
metastatic, may be simulated closely by syphilitic disease, and I have 
known of biopsies done because of the radiologic diagnosis of tumor in the 
presence of positive serologic tests for syphilis. Osteitis involving the 
medial end of the clavicle may suggest arthritis of the sternoclavicular 
joint, as well as erosion by an aortic aneurysm. The latter may be particu- 
larly simulated by gummatous osteitis of the sternum. Syphilitic lesions of 
the facial bones most commonly lead to a diagnosis of retrobulbar tumor, 
empyema of paranasal sinuses, or carcinoma of the antrum. Syphilitic 
osteitis of the bony nasal septum (perforation) or of the nasal bones 
(saddle-nose, Fig. 12) has long been a hallmark of syphilis; less common is 
involvement of the hard palate with the implied differential diagnosis of 
carcinoma of the oral mucosa (Fig. 10). The severe and persistent pain 
accompanying gummatous osteitis of the calvarium not uncommonly has 
been misinterpreted in terms of disease of the meninges or of brain tumor, 
and the radiologic examination in some cases may represent difficulties in 
the differential diagnosis from metastatic carcinoma and multiple myeloma 
(Fig. 7). Ulceration accompanying periostitis and gummatous osteitis of 
the tibia is not infrequently considered to represent stasis ulceration 




Figure 9. Syphilitic destruc- 
tion beginning in the cartilaginous 
nasal septum leading to loss of the 
tip of the nose. 



1 




678 



R. H. Kampmeier 




Fig. 10 Fig. 11 

Figure 10. Syphilitic destruction of the palatal bones. (Kampmeier: Physical 
Examination in Health and Disease. Courtesy of F. A. Davis Co.) 

Figure 11. Large perforation of the soft palate following gummatous ulceration. 
(Kampmeier: Physical Examination in Health and Disease. Courtesy F. A. Davis Co.) 

accompanying varicose veins. Fortunately, involvement of the small bones 
of the hands and feet is uncommon, and rarely forces a differentiation 
between one of the art hri tides— rheumatoid, tuberculous or gouty — and 
syphilitic disease of phalanges. 

Results of Treatment. Specific therapy is usually followed by complete 
healing and restoration of bone without x-ray evidence of residua unless 
the process was a proliferative (sclerosing) one. 



Late Syphilis of Mouth and Pharynx 

Gummatous disease of structures of the mouth and throat are much 
less frequent than late lesions of the skin and bones. Among examples 
encountered in the Vanderbilt University Hospital Syphilis Clinic the most 
frequent were gummatous disease of the soft palate, tonsillar fossa and 
posterior pharyngeal wall. Involvement of the hard palate is not uncommon 
and probably occurs as osteitis or periostitis of the palatal bones since 
perforation is the usual outcome (Fig. 10). The lips and tongue are rarely 
the site of gummas. 

Clinical Picture. Gummatous infiltration of structures of the throat, 
soft palate, tonsillar fossae or pharyngeal wall provide the complaint of 
chronic sore throat — weeks or even months of symptoms characterized 
mainly by discomfort or difficulty in swallowing rather than actual pain, 
representing a mechanical disability rather than suggestive of the inflam- 
mation of acute disease. Examination in a nonulcerative stage shows 



The Late Manifestations of Syphilis 679 

thickening or infiltration of the structure involved — the palate, uvula, 
tonsil, or other structure — with pallor, suggesting edema, but with firmness 
to the palpating finger. If treatment is not given at this stage, ulceration 
is inevitable with extensive destruction at times, the extent dependent 
upon the time of recognition of the cause and proper treatment. Perforation 
of either the hard or soft palate, deforming scars of tonsillar areas and 
deep depressed scars of the posterior pharyngeal wall point to a former 
destructive gummatous ulcer, and are as suggestive of syphilis as a positive 
blood test (Fig. 11). 

Gumma of the lip not infrequently is part of a tertiary syphilid of 
the face, though it may appear independent of such a lesion (Fig. 12). 
Gumma of the tongue appears as a tumor deep within the substance of 
the tongue and if untreated will lead to ulceration (Fig. 13). It responds 
promptly to antisyphilitic treatment usually with loss of tissue and then 
often with extensive scar. 

Differential Diagnosis. Differentiation of a chronic tumefaction or 
ulceration involves but a few lesions, tumor in the main of malignant 
nature, or of other chronic granulomatous disease, most specifically tuber- 
culosis. Knowledge of the clinical course and the characteristic symptoms 
and signs of these diseases, including the syphilitic granuloma, and atten- 
tion given to serologic tests for syphilis, usually point the way to treatment 
and prompt resolution, which is diagnostic. 

Syphilis of the Respiratory Tract 

Serious attention need only be given to the involvement of one struc- 
ture — the larynx. Gummatous infiltration of the laryngeal mucosa, with 
or without ulceration, was not an infrequent diagnosis made by the 
otolaryngologist in former years. The response of these lesions to anti- 
syphilitic treatment is prompt, satisfying and diagnostic. Neglected disease 
may lead to extensive ulceration, and sloughing of laryngeal cartilages with 
severe deformity of the larynx. The differential diagnosis involves particu- 
larly carcinoma and tuberculosis. The clinical characteristics of these 
diseases generally permit the experienced laryngologist to differentiate 
them from gummatous disease. The epiglottis may be involved in the 
ulcerative process and we have seen it even without the need of a laryngeal 
mirror, merely by traction on the tongue. 

Late lesions of the respiratory passages below the larynx and of the 
lung are very rare and difficult of confirmatory diagnosis. That they do 
occur has been documented pathologically. The late lesions of syphilis of 
the lung may appear either as a solitary tumor or infiltrate rather sharply 
localized and of several centimeters in diameter, or as a diffuse infiltrative 
process of major extent. Only rarely is the diagnosis established by patho- 
logic examination; the etiology of the lesion may be questioned if based on 
its resolution following the use of antibiotics. It is only the disappearance 



680 



R. H. Kampmeier 



Fig. 12 



Fig. 13 





Fig. 14 

Figure 12, Gumma of the lip and accompanying involvement of the adjacent skin. 
(Note the saddle-nose deformity as the result of previous osteitis of the nasal bones.) 

Figure 13. Gumma of the tongue. (Kampmeier: Physical Examination in Health 
and Disease. Courtesy F. A. Davis Co.) 

Figure 14. Gumma of lateral aspect of the thigh, above the knee, 3 years after 
healing of the gumma of Figure 13 subsequent to penicillin. Lesion of thigh was healed 
by diagnostic bismuth therapy before penicillin therapy was again begun. 






The Late Manifestations of Syphilis 681 

of a solitary lesion under bismuth therapy which will permit the presumed 
diagnosis of gummatous lesion of the lung. 

In several patients in our clinic, because of symptoms referred to the 
respiratory tract, bronchoscopic examination has shown infiltration of the 
bronchial mucosa, but never have we had success in the specific histo- 
pathologic diagnosis of syphilis, rather a description of ''chronic inflam- 
matory reaction" of the mucosal biopsy. The response to metal therapy 
and subsequent resolution of the lesion symptomatically, confirmed in 
several instances by subsequent bronchoscopic examinations, made it seem 
probable that just as in the larynx gummatous infiltration of the bronchial 
mucosa may occur. The certain diagnosis has been impossible in each 
instance. 



Syphilis of the Gastrointestinal Tract 

The most common clinically recognized manifestation of late syphilis 
in these structures has been gummatous hepatitis. Few clinicians have not 
counted at least one such instance in their experience. It was by far one of 
the common visceral lesions of the past. Empiricism is usually based on 
some fact! A half-century ago it was said to be not uncommon practice in 
the South, with its large colored population and high incidence of syphilis, 
that if low-grade fever was encountered empiric treatment consisted first 
of quinine and, if there was no response in the febrile course, mercury and 
iodides were next exhibited. In the autopsy room of any large hospital in 
decades past the incidental finding of hepatic gummas or the scarred liver 
of hepar lobatum was not uncommon, a fact within my experience at the 
Charity Hospital of New Orleans 30 years ago. 

The symptomatology which brings the patient with gummatous hepa- 
titis to the physician are epigastric discomfort and tenderness. More often 
than not the patient is asymptomatic but becomes aware of a mass in the 
abdomen, often merely by accident (Fig. 15). Low-grade fever is a common 
accompaniment, probably the result of the necrosis which commonly 
occurs in the gummas which, in the liver, are among the largest encountered 
incidentally at autopsy. In patients with gummatous hepatitis, spleno- 
megaly and anemia are common. The differential diagnosis in the presence 
of a nodular liver involves more often than not carcinoma, either primary 
or metastatic, more rarely cysts of congenital origin, and very rarely in 
this country echinococcal cyst. 

Syphilis of the stomach manifested by a mass in the epigastrium and 
a large ulcer shown radiologically, often with obstruction, has been docu- 
mented many times and in many hospitals. The symptoms, as might be 
anticipated, are likely to be interpreted as those of carcinoma or as obstruc- 
tion accompanying a peptic ulcer, and the radiographic findings commonly 
seem to substantiate one or the other clinical impression. Most of the 
reported cases, which have not been inconsiderable in the literature, have 



682 R. H. Kampmeier 




; I 



Figure 15. Enlarged liver with large nodules; note splenomegaly. (Kampmeier: 
Physical Examination in Health and Disease. Courtesy F. A. Davis Co.) Same patient 
as in Figure 7. Liver receded to the costal margin subsequent to antisyphilitic treatment. 

been diagnoses made on surgical specimens. Rarely the esophagus may be 
involved by a gummatous process, the most common interpretation of 
clinical and radiographic findings being that of malignancy.'^ 



Late Lesions of the Eyes 

Iritis. This or iridocyclitis is not unusual as an accompaniment of 
secondary syphilis, particularly as a relapse phenomenon, often unaccom- 
panied by the other clinical manifestations of rash or lesions of the mucous 
membrane. However, it also may represent a late evidence of syphilitic 
infection. The symptomatology of iritis irrespective of its etiology consists 
of photophobia, pain, and dimness of vision. The characteristic circum- 
corneal injection and edematous iris again are nonspecific. Adhesions to 
the anterior lens capsule commonly occur, again irrespective of the cause, 
and not uncommonly leave sl fixed pupil, an item of significance at times 
in the diagnosis of late syphilitic disease of other anatomic structures. 

Chorioretinitis. Syphilitic inflammation of the choroid and the deli- 
cate overlying retina is not an unusual late lesion. Foci of exudate are 
obvious on ophthalmoscopic examination; if resolution and healing have 
occurred, the white sclera is evident with scattered areas of choroidal 
pigment. The visual loss depends upon the extent and location of retinal 
involvement and resulting scotomas. Though other diseases produce similar 
lesions, evidence of former chorioretinitis presents a hint that the treponeme 
may have passed this way. 

Iritis is particularly stubborn to treatment. On the other hand, chorio- 
retinitis responds readily to antisyphilitic treatment, but because of the 
delicate retinal tissue a Herxheimer reaction may lead to a more extensive 
functional loss than from the disease per se, untreated at the moment. 



The Late Manifestations of Syphilis 683 

Among the cases of late benign disease encountered in the Vanderbilt 
University Hospital Syphilis Clinic these two manifestations in the eye 
made up some 10 per cent of late benign lesions.*^ (Primary and secondary 
optic atrophy and neuroretinitis do not fall into the category of late benign 
syphilis, representing manifestations of disease of the central nervous 
system.) 

Miscellaneous 

The late benign lesions of syphilis of the skin (Olansky), of the skeletal 
system, the mouth and oropharynx, the larynx, the liver and stomach, and 
the eyes, already considered, represent the more common sites of the 
disease. 

It may be said, however, that no tissue of the body is immune to 
the late manifestations of syphilis, and that literally every organ or struc- 
ture of the body has been reported to be the site upon occasion of either 
the proliferative or the gummatous lesion. Though involvement in the 
remaining bodily structures have been documented, they are uncommon. 
All of the glands, both with exocrine or endocrine function, have been 
reported to be involved at some time. Syphilitic disease of the pituitary, 
the thyroid, adrenal, ovaries, testes and pancreas have been proved. (I 
have seen Addison's disease due to such disease in two patients, proved at 
necropsy. Gumma of the testicle has appeared in our clinic. Gumma of the 
thyroid and of the breast tissue have fallen within my experience.) 

Late syphilitic lesions of the lymphoid structures, such as of the nodes 
and spleen, have been reported, and we have seen such involvement of the 
lymph nodes. Gummas of the kidney have been reported as well as of the 
urinary bladder. Proliferative disease of the mediastinum was a recognized 
entity of the past and was encountered by us, if our diagnoses were correct. 
Gummatous tumors of the brain and of the myocardium have been 
repeatedly documented in the literature, and encountered occasionally in 
our own hospital. The spinal cord is rarely involved by a gumma. 

Paroxysmal cold hemoglobinuria due to an autohemolysin may occur 
under a number of circumstances. Among the instances of this uncommon 
disease, syphilis is a relatively frequent cause, especially of the congenital 
variety. It responds to antisyphilitic treatment. 

Serologic Findings 

In Rosahn's^ autopsy studies at Yale, of the 380 syphilitics coming to 
autopsy 197 had positive and 116 negative serologic tests at the time of 
the last hospital admission. Positive tests were clearly more frequent than 
negative tests in cases in which there were anatomic lesions. Nevertheless, 
about a fourth of all syphiUtics with anatomic lesions at autopsy had 
negative tests at the time of their last admission, though conversely about 
one-half of those with positive tests had no histopathologic evidence of 
syphilis. 



684 R. H. Kampmeier 

Generally speaking, it is to be anticipated that the late benign lesions 
of syphilis should be accompanied by a high incidence of positive serologic 
tests. This might be anticipated particularly in the instance of gummas, 
and especially those which involve parenchymatous organs. It is my experi- 
ence that widespread involvement of a parenchymatous organ is associated 
with a positive test in high dilutions. It is also my impression that this is 
true particularly in syphilitic hepatitis; it is well shown also with the 
extensive involvement of the cerebrum that is general paresis. On the 
other hand, a sharply localized gummatous process unaccompanied by 
widespread involvement of tissues might by chance give a negative test. 
This we have encountered in syphilitic disease of bone upon occasion. 
Conversely, however, an apparently negative reaction may represent a 
zone phenomenon in a blood positive in high titer. This is illustrated in 
what was obviously osteitis of the tibia due to congenital syphilis. The 
clinical diagnosis was made with slight confirmatory radiologic evidence. 
The serologic tests were as follows : 

May- August, 1953. A 15 year old Negro boy was studied in the Vanderbilt 
University Hospital Clinic for ''idiopathic" hypochromic anemia (mild) of unknown 
cause. Kahn and VDRL tests — negative. 

June 16, 1954- He entered the emergency room for pretibial pain and tender- 
ness. Temperature 100° F. Kahn — doubtful; VDRL — positive; Wassermann — posi- 
tive. 

June 22. Kahn and VDRL — negative. Radiologist reported bilateral tibial 
cortical thickening compatible with congenital syphilis. 

June 21^.. Kahn and VDRL — negative; Wassermann — anticomplementary. 
(Spinal fluid negative.) 

June 29. Quantitative VDRL — negative in dilutions 1 :2 through 1 :32; posi- 
tive 1:64 through 1:256; negative beyond this. Quantitative Kahn — doubtful in 
dilutions 1:1 through 1:4; positive 1:8 through 1:256; doubtful 1:512 through 
1:2048; negative 1:4096. 

Symptomatic improvement followed treatment with penicillin. Variability in 
positive, negative and doubtful serologic reports and positivity in high dilutions 
continued through mid-October 1954. Thereafter consistent positivity in VDRL, 
Kahn and Wassermann tests continued through the last recorded test in December 
1957. 

Treatment 

In general the treatment of late benign syphilis is satisfactory, although 
in the days of metal therapy an incidence of relapse within the several 
years after treatment for a previous gumma occurred in some 10 per cent 
of cases, and irrespective of seroreversal or serofastness.^ (This was even 
greater if treatment had been inadequate or erratic.) This has been true 
only in a few instances of gumma treated by penicillin (Figs. 13, 14). The 
blood almost always remains serofast. 

Treatment with 6 to 9 million units is accepted as adequate treatment. 
To avoid a Herxheimer reaction in the delicate retina in the treatment of 
chorioretinitis, I have preferred to resolve the lesion first with aqueous 
bismuth before beginning penicillin therapy. 



The Late Manifestations of Syphilis 685 

CARDIOVASCULAR SYPHILIS 

History. As might be guessed, historical descriptions of the complications of 
syphiUtic aortitis began with the descriptions of the gross findings in persons having 
saccular aneurysms. In the second century a.d. Galen recognized aneurysms result- 
ing from trauma to peripheral arteries.^" Four centuries later Aetius wrote on the 
same topic, but also referred to rupture of an artery without external injury, as 
seen in the neck, saying ". . . . it very commonly happens to women during par- 
turition, on account of the forceful detention of spirits." Whether this might have 
referred to aneurysms of the aorta, innominate or carotid is not clear, but if it did, 
aneurysms in a child-bearing age would without question need to be of syphiUtic 
origin. Fernel, in 1542, gave us the first real description of internal aneurysms of 
large vessels in the chest and abdomen. Ambroise Pare later in the sixteenth century 
recognized the relationship of aneurysm to syphilis and related it to the "unction 
(mercury) and sweat in the cure of French disease." 

Good descriptions of various pathologic and clinical aspects of aneurysms 
appeared during the eighteenth century, and not infrequently related them to 
syphilis. In 1761, Morgagni wrote the first good description of the gross pathology 
which characterizes syphilitic aortic disease, describing a small aneurysm of the 
sinus of Valsalva with rupture into the pericardium, as follows: "That is to say in 
some places whitish marks of future ossification occurred ; in others small foramina, 
as it were, had begun to be formed; and in still other places were parallel furrows 
drawn longitudinally; and in this manner was the surface of the artery unequal 
here and there." In the nineteenth century a number of papers described the various 
symptoms and signs of aneurysms which have always been the dehght of those 
interested in physical diagnosis, especially before the days of dependence upon the 
roentgenogram. The first scientific paper attempting to prove that syphilis was the 
cause of aortic aneurysm appeared in 1875 by Welch," which was protested and 
unacceptable to prominent English physicians. 

Dohle,^2 in 1895, described the hallmarks of the histopathology of syphilitic 
aortitis. A year after the description of the Spirochaeta pallida by Schaudinn and 
Hoffman, in 1905, Reuter^^ described the organism in the wall of the aorta in 
aortitis. Thus, through study of aneurysms developed an understanding of the 
etiology, pathogenesis and clinical manifestations of the compUcations of syphilitic 
aortitis. 

The basic lesion of acquired cardiovascular syphilis is aortitis. (It is 
not known to occur in congenital syphilis, and in the Oslo Study^ was not 
found even in acquired syphilis if it occurred before age 14.) Though the 
diagnosis of uncomplicated aortitis is essentially a pathologic one, the 
clinical recognition of its complications, as aneurysm, aortic insufficiency 
or stenosis of coronary orifices, usually is quite easy. These are the lesions 
which make syphilitic cardiovascular disease a disabling and fatal one. 
Warthin's^"* description, in 1931, of finding treponemes in the myocardium 
and the pathologic diagnosis of syphilitic myocarditis is accepted by few 
pathologists. There is a rare case, of which there have been two or three at 
the Vanderbilt University Hospital, in which it seems probable that 
myocarditis has occurred in the invasive stage of early syphilis, on the 
basis of clinical findings, changing electrocardiographic patterns and re- 
sponse to treatment. The etiology in such cases would be diflScult to 
establish. 



R. H. Kampmeier 

On the other hand, gummatous myocarditis is a recognized pathologic 
lesion and well over a hundred cases have been documented in the literature. 
Most of these lesions have occurred in the wall of the left ventricle and 
have commonly been associated with bundle branch block; electrocardio- 
graphic changes may suggest myocardial infarction. Instances of gumma 
of the intraventricular septum have been reported, accompanied by com- 
plete heart block. (Two such cases have been recognized, with proof at 
autopsy, at our institution. i^) Rarely gummatous myocarditis obstructs 
one or both coronary arteries. 

Pathology 

The course of syphilitic aortitis most probably represents an early 
invasion of the aortic wall by the Treponema pallidum during the early 
years of infection when there is recurrent spirochetemia. Just as invasion 
of the central nervous system may occur early in the secondary stage or as 
part of secondary relapse, so most probably the vascular structures are 
invaded either via mediastinal lymphatics as part of the characteristic 
lymphadenopathy, or directly through the vasa vasorum which are particu- 
larly numerous in the ascending and transverse segments of the aortic arch. 
Aortitis is more frequent in these portions of the arch. (The arterial lesions 
of syphilis are limited in the main to the large blood vessels, in which there 
is an arterial blood supply to the wall by vasa vasorum.) 

Irrespective of the route of invasion, characteristic lesions of obliterat- 
ing endarteritis of the vasa vasorum, infiltration by lymphocytes and 
plasma cells, and necrosis and fragmentation of the elastic tissue in the 
media, accompanied by lymphocytic exudate and often miliary gummas of 
the adventitia, present a basic process which goes on over the years and 
may eventually lead to such a loss of elasticity of the aortic wall as to 
permit dilatation of the aortic arch or, if there is focal weakening, the 
development of an aneurysmal sac (Fig. 16). Dilatation of the aortic ring 
may be accompanied by the characteristic separation and sagging of the 
valve commissures, and the inflammatory lesion of the aortic wall may 
involve the valve leaflets as well. These changes in the valves and/or 
dilatation of the aortic ring explain the aortic regurgitation. Not unusually 
changes in the aortic wall cause deformity or narrowing of the coronary 
ostia impairing coronary flow manifested by myocardial insufficiency or 
by angina. (Some 25 per cent of the patients with aortic insufficiency on 
my service at Charity Hospital, New Orleans, revealed at autopsy involve- 
ment of one or both coronary ostia.) As was indicated in the graphic 
demonstration of the natural course of untreated syphilis, progressive 
disease in the aortic wall continues for from 10 to 30 years after infection 
before the complications of aortitis may become manifest (Fig. 2). 

Incidence of Aortitis and Its Complications 

It is difficult to evaluate the incidence of complications of syphilitic 
aortitis from either hospital statistics or private practice. The figures from 



The Late Manifestations of Syphilis 



687 




Figure 16. Syphilitic aortitis with the characteristic changes of its compHcations. 
This shows the classic dull gray, wrinkled and puckered areas of intima above the 
aortic valve (A); the thickened, rolled eges of the aortic cusps (B); the lowered attach- 
ment of the commissures as related to the level of the coronary ostia, and their separa- 
tion (C); the narrowed coronary ostium (D); the thickening of the endocardium on the 
interventricular septum (E). (Kampmeier: Essentials of Syphilology.^ Courtesy J. B. 
Lippincott Co.) 



688 R. H. Kampmeier 

Table 4. Anatomic Findings (Cardiovascular) in 77 Patients with Untreated 
Syphilis Among \\ horn 106 Lesions Were Found at Autopsy* 

NUMBER OF LESIONS FOUND 

In 31 patients In all 77 

TYPE OF LESION In 46 patients with syphilitic patients 

dying primarily changes a sub- 



of syphilis sidiary finding No. Percent 



Aortitis with or without valvulitis 26 29 55 

Aneurysm of arch 8 1 9 

Aneurysm of abdominal aorta 1 2 3 

Coronary arteries 4 4 

Aortitis of leg vessels 3 3 

Cerebral arteritis 2 2 

Ruptured aneurysm of arch 9 9 

Ruptured aneurysm of innominate artery 1 1 

Ruptured cerebral aneurysm 2 2 

All cardiovascular 56 32 88 83.0 

* Modified from Rosahn.^ 

the large city hospitals caring for the indigent are weighted by an inordinate 
incidence of advanced disease, and particularly by a higher incidence of 
syphilis. On the other hand, the reported incidence of cardiovascular 
syphilis in private patients is frequently too low, either through misdiag- 
nosis or through dishonest reporting of the cause of death to save the 
family of the deceased from the stigma of syphilis, or to circumvent riders 
in insurance policies which exclude venereal disease from the benefits of 
the policy. 

The best figures we have then, are those from the Oslo study by 
Clark and DanboftJ^ in which they found the following: in 303 males 
and 584 females, aortic insufficiency in 7.3 and 3.3 per cent respectively; 
saccular aneurysm in 3.6 and 1.5 per cent; ostial stenosis in 0.7 and 0.3 
per cent, and uncomplicated aortitis found at death in 0.7 and 0.0 per cent 
respectively.* This provides an incidence of cardiovascular syphilis of 12.3 
per cent in males and 5.1 per cent in females, or a total of 10 per cent in 
887 persons. It is interesting that this figure is quite comparable to the one 
accepted for years for the development of complications of aortitis — namely 
in about 10 per cent of people with untreated syphilis. 

Nothing is to be gained by citing additional studies of incidence of 
aortic insufficiency and/or aneurysms of the aorta from hospital statistics, 
of which there were many compilations in the past. If one considers rather 
the evidence as shown at autopsy that uncomplicated aortitis does exist, 
as pointed out by Rosahn and others, and that the complications of 
aortitis — aortic regurgitation, saccular aneurysm and involvement of the 
coronary ostia — may occur, enough has been said for this discussion 
(Table 4). 

*See paper by Clark and Danbolt in this volume. 



The Late Manifestations of Syphilis 689 

Clinical Considerations 

Uncomplicated Aortitis. Much has been written about the possibility 
of recognizing this condition upon physical examination, with emphasis 
particularly upon changes in the aortic second sound. In spite of a long 
interest in the details of the physical examination, I have never thought 
that the diagnosis of uncomplicated aortitis is possible by physical means 
alone. Though aware of changes in the aortic second sound, it has been 
impossible for me to accept their diagnostic specificity. An analysis was 
made of the findings recorded in the clinical records of 33 cases of uncom- 
plicated aortitis as diagnosed at necropsy among 168 syphilitics, on whom 
postmortem examinations were done at Vanderbilt University Hospital. ^^ 
Half of these 33 patients had had no symptoms of cardiovascular disease; 
in the remaining half there was pathologic evidence of cardiovascular 
disease which offered a better explanation of symptoms and signs than did 
uncomplicated aortitis. By contrast with these, among the 168 syphilitics 
were 30 without pathologic evidence of aortitis, but in whom other cardio- 
vascular disease accounted for a greater number of the symptoms and 
signs which have been considered to point to a diagnosis of uncomplicated 
aortitis. White and Wise^^ and others have agreed in this attitude that the 
diagnosis of cardiovascular syphilis in the absence of aortic regurgitation, 
aneurysm or narrowing of the coronary artery is for all practical purposes 
impossible. Even controlled x-ray examinations by fluoroscopy and films 
of men having late latent syphilis have been unrewarding attempts at an 
early diagnosis of uncomplicated aortitis. To the contrary. Rich and 
Webster, ^^ in reporting upon the natural course of aortitis in 141 patients, 
believed that the clinical diagnosis can be made. 

Aortic Insufficiency. As was indicated on the graph, the most common 
complication of syphilitic aortitis manifests itself from 10 to 20 years after 
infection (Fig. 2). In the past most cases appeared between the ages of 35 
to 50 years in white patients. Among Negroes the age incidence was some- 
what earlier because of earlier sexual maturity and an earlier age incidence 
of infection.* Many authors have pointed to the possible effect of heavy 
labor in the development of the complications from syphilitic aortitis, 
speculating as to the part played by the Valsalva effect of lifting and other 
arduous occupations. All studies of the incidence of aortic insufficiency 
and aneurysm point to a greater frequency in men than in women. Cochems 
and Kemp^^ reported an incidence of serious cardiovascular syphilis in 
14 per cent of those doing heavy labor and in only 8.7 per cent of those in 

* It is the duration of the disease and not the actual age which is significant, a fact 
to be borne in mind in coming years because of the current higher incidenpe of syphilis 
in teen-agers than in past decades. As this untreated group moves into the second 
decade of its infection, the complications of aortitis may appear at an earlier age than 
in past years. However, it must be recollected that in the Oslo Study cardiovascular 
disease did not occur if syphilis was acquired before age 14 which, along with the absence 
of aortic disease in congenital syphilis, points to some unexplained immunity of the 
large blood vessels to syphilitic invasion in youth. 



690 R. H. Kampmeier 

sedentary occupations. In our study of 163 patients with syphilitic aortic 
insufficiency at Vanderbilt University Hospital among 2951 cases of late 
syphilis, we believed that the 91 instances in Negro males, 37 in Negro 
females, 27 in white males and eight in white females emphasized the 
probability that heavier work was a factor in the development of this 
complication of syphilitic aortitis. ^^ Though pointing out the difficulties of 
proving the untoward effect of heavy labor, Webster and associates'^ 
believe it to be a probable etiologic factor. 

The physical findings of aortic regurgitation will not be considered in 
detail in this discussion. The characteristics of the murmur, its radiation 
and attendant physical, radiologic and electrocardiographic changes are 
fully described in the standard reference books on internal medicine or 
physical diagnosis. 

It is worthy of note that in all reported studies on this complication 
of aortitis a certain number of diagnoses are made in the asymptomatic 
stage. (In our series of 163 patients the murmur was found incidental to a 
routine examination and in an asymptomatic phase of the disease in 
15 per cent.) It is also significant that not infrequently the clinician, as he 
follows the course of the patient, will record progression of aortic regurgi- 
tation (in contrast to that of rheumatic origin) with increasing intensity 
and more extensive radiation of the murmur, widening of the pulse pressure, 
an elevation of the systolic pressure and depression of the diastolic phase, 
and the gradual development of the peripheral manifestations of a widening 
pulse pressure. The fluoroscopic demonstration of increased pulsation 
and/or dilatation of the ascending arch is common. The development of 
anginal episodes as the disease progresses in not infrequent, probably as 
much the result of decreased coronary flow secondary to the ill-sustained 
intra-aortic pressure during diastole, as the narrowing of the coronary ostia 
commented upon above. 

Prognosis in syphilitic valvular incompetence is variable. In patients 
in whom the diagnosis is made before subjective symptoms develop, and 
especially in the younger group, the prognosis is relatively good, life 
extending beyond ten years in a third of the patients. '^ On the other hand, 
it seems that in many of those who have developed symptoms, death occurs 
within three years from the onset of symptoms. '^ There is no good evidence 
that antisyphilitic treatment prolongs life in those who have established 
aortic regurgitation. (Treatment of the complications of syphilitic aortitis 
is prophylactic — the treatment of latent syphilis, and thus aortitis, before 
complications develop.) 

The differential diagnosis in the main involves the differentiation from 
aortic insufficiency of rheumatic origin, particularly intriguing if the mitral 
diastolic murmur of the Austin-Flint variety accompanies syphilitic aortic 
regurgitation, thereby simulating the combined rheumatic lesions of mitral 
stenosis and aortic insufficiency. Only rarely do diastolic murmurs resulting 
from longstanding and marked hypertension or calcific aortic valvular 



The Late Manifestations of Syphilis $91 

disease pose diagnostic problems in the patient aged 35 to 50. Again the 
details of differential diagnosis will be found in the standard texts on 
medicine and physical diagnosis. 

The accompaniment of cardiovascular syphilis by cardiac disease of 
rheumatic, congenital or arteriosclerotic origin is described periodically. 
The complication of atrial fibrillation points to a nonsyphilitic factor in 
the apparent heart disease. With extension of life expectancy the recogni- 
tion of syphilitic heart disease is becoming more frequent in the elderly.^^ 

Stenosis of the Coronary Ostia. As was implied above, if syphilitic 
aortitis involves the coronary ostia with narrowing of one or both orifices, 
deficient blood flow may lead to some degree of mycocardial ischemia, 
reflected as angina. This condition is to be considered in the young syphilitic 
who has angina but does not have hypertension or other evidence of myo- 
cardial disease. An absolute diagnosis is difficult. Clinical manifestations as 
a result of such syphilitic disease may either be ameliorated as a result of 
antisyphilitic treatment, or may actually appear as a Herxheimer effect — 
a localized exacerbation of the process immediately following antisyphilitic 
treatment. 

Aortic Aneurysm. True aneurysm as the result of syphilitic aortitis 
in most instances is of the saccular type, a circumscribed bulging of the 
wall of a vessel growing to a sac connected to the lumen of the artery usually 
through a definite ring; less commonly there may be a fusiform dilatation 
of a portion of a vessel, more often of the aorta. (Dissecting aneurysms are 
not of syphilitic origin.) In this country aneurysms generally have been 
considered to have about one-fourth the frequency of syphilitic aortic 
regurgitation, though in the Oslo series of untreated syphilitics saccular 
aneurysm occurred about one-half as often as aortic regurgitation, in both 
sexes. 

Saccular aneurysms of the ascending arch of the thoracic aorta are 
associated with a higher incidence of aortic regurgitation than are those of 
the transverse or descending arches, because of the frequency of aortitis of 
the ascending arch. My study of 633 saccular aneurysms of the thoracic 
aorta again emphasizes the probable role of occupation as a predisposing 
factor in the development of this complication of syphilitic aortitis. ^^ It 
reflects itself in the higher incidence in the male sex as compared to the 
female (6:1), and also at an earlier age in the Negro patient than the white 
suggesting probably infection at an earlier age, as well as a higher frequency 
of heavy labor in the Negro race. (These were the findings among the 
patients admitted to Charity Hospital (New Orleans) in the earlier decades 
of this century.) The highest rate of incidence in both Negro men and 
women appeared between ages 36 and 45. In white men the peak incidence 
appeared between ages 46 and 55, and in white women an equal incidence 
in this decade and in the decade 56 to 65. 

The clinical diagnosis of aneurysm of the thoracic aorta is usually not 
difficult in these days of the almost daily use of the x-ray in diagnosis. 



692 R. H. Kampmeier 

Earlier the diagnosis of aneurysm commonly offered the greatest test of 
clinical acumen in taking the history, doing the physical examination and 
their interpretation. The wide spectrum of clinical manifestations based on 
history and physical examination may be summarized by imagining a 
pulsating tumor varying in size from a few centimeters to 15 or more 
centimeters in diameter and in intimate relationship to the vital structures 
in or adjacent to the mediastinum. If one recognizes the structures which 
might be affected by pressure, as the trachea, major bronchi, lungs, 
esophagus, pulmonary arteries, vagus and sympathetic nerves, laryngeal, 
recurrent laryngeal and intercostal nerves, the diaphragm, and indirectly 
the stomach, one can imagine the whole possible gamut of symptomatology 
resulting from an aneurysmal sac (Fig. 17). One may add to this the erosion 
of bony structures by the pulsating mass of the vertebra (with involvement 
of the spinal roots), ribs, clavicle and sternum (Figs. 18 and 19). Though 
the roentgenogram usually makes the diagnosis, it is well to recall that a 
small aneurysm, not demonstrable, may yet impinge upon a vital structure 
at some strategic point to produce symptoms; even large aneurysmal sacs 
may be missed if there is pulmonary consolidation, or pleural effusion. 

Aneurysms of the abdominal aorta are much less frequent than those 
of the thoracic aorta. They occurred only about one-tenth as often in the 
Charity Hospital series. Those of syphilitic origin arise characteristically 
above the origin of the renal arteries. The symptoms result from pressure 
either upon portions of the gastrointestinal tract, with disturbance in 
function, or from erosion of the upper lumbar spine with pain from involve- 
ment of the respective nerve roots. In a study of 73 patients a palpable 
pulsating tumor was found in 47, or 60 per cent of cases. The mass may 
lie high under the diaphragm and then may not be found by palpation. 
The high location of the syphilitic aneurysm is well demonstrated in 18 
instances in which erosion of vertebrae was shown by the x-ray. The 
vertebra most frequently involved is the first lumbar, and the least frequent 
the eleventh dorsal and the third lumbar, with equal incidence of involve- 
ment of the twelfth dorsal and second lumbar vertebrae. With good 
lighting and careful inspection, pulsation may be recognized posteriorly to 
the left of the spine just below the level of the twelfth rib. 

The prognosis in aortic aneurysm is gloomy, death occurring commonly 
within a matter of months after the development of symptoms and estab- 
lishment of the diagnosis. Only rarely does one encounter calcification in 
the laminated clot which is so characteristic of the saccular aneurysm, and 
thus ''healing" of the lesion. In only several instances have I seen the 
progression of an aneurysm halted for years by a deposit of calcium. 

Differential Diagnosis. It has already been said that the diagnosis of 
syphilitic saccular aneurysm of the thoracic aorta can be made with 
relative ease by the x-ray examination, and that probably today most are 
discovered merely through the routine use of the x-ray. For the interested 



The Late Manifestations of Syphilis 



693 




Fig. 17 Fig. 18 

Figure 17. Aneurysm of the ascending portion of the aortic arch. 
Figure 18. Aneurysm of the ascending arch with erosion of clavicle and ribs. 



Figure 19. Erosion of spine and ribs by 
aneurysm of the descending aortic arch. 
(Kampmeier: Essentials of Sy philology.*^ Cour- 
tesy J. B. Lippincott Co.) 




694 R. H. Kampmeier 

Table 5. Syphilitic Aneurysms of the Abdominal Aorta: Distribution as to 
Age, Sex and Color^^ 



AGE IN YEARS 


NEGRO 
MALES 


WHITE 
MALES 


NEGRO 
FEMALES 


WHITE 
FEMALES 


20 to 24 


3 


_ 


3 


_ 


25 to 34 


8 


5 


3 





35 to 44 


20 


2 


2 





45 to 54 


9 


3 


— 


1 


55 to 64 


4 


1 


— 


2 


65 and up 


1 


— 


— 


— 


No age given 
Total 


1 
46 


11 


T 


3 



physician it should be pointed out that in the differential diagnosis of 
mediastinal disease, with involvement of one or more anatomic structures, 
saccular aneurysm must be included along with other space-occupying 
lesions. Pulsation found at fluoroscopy, if not on physical examination, 
usually is diagnostic; in an occasional instance a firm laminated clot may 
prevent pulsation. I have knowledge of good surgeons exploring the 
mediastinum expecting to attack a solid tumor, and encountering an 
aneurysmal sac which, upon manipulation resulted in sudden rupture and 
death. This merely points up the uncertainty of an absolute diagnosis. 

Today the frequency of arteriosclerotic aneurysms of the abdominal 
aorta and the lessened number of syphilitic ones has led some authors to 
declare that syphilitic aneurysms of the abdominal aorta do not occur. The 
thoughtful clinician will not make such an assumption, particularly if he 
will recall the anatomic site of the syphilitic aneurysm as above the level 
of the renal artery, and the arteriosclerotic one usually below this level. 
He also should consider the patient's age. Arteriosclerotic aneurysm of the 
abdominal aorta occurs in an older age group, the syphilitic one in a 
younger group. This is emphasized in the accompanying table (Table 5). 
The present-day confusion on this topic has arisen because of the decreasing 
frequency of the late lesions of syphilis and an increase in the aged popula- 
tion. Furthermore, the refinements of surgery have stimulated accurate 
diagnosis of arteriosclerotic aneurysms of the abdominal aorta for their 
surgical removal. 

Serologic Findings 

It is important to emphasize that a fair percentage of patients who 
are ill and are dying of syphilitic aortic insufficiency have negative serologic 
tests, whether of the flocculation or complement fixation variety. Rosahn^ 
found in his autopsy studies on 380 syphilitics, that 197 had positive 
serologic tests, and 116 negative tests at the time of the last hospital 
admission. He found that about one-fourth of all syphilitics with specific 
anatomic lesions had negative blood tests on the last admission to the 



The Late Manifestations of Syphilis 695 

hospital. Of those who died primarily as the result of syphilis, about 80 per 
cent had positive tests. This is in contrast to an incidence of anatomic 
changes of syphilis in only about one-sixth of those who had had serologic 
reversals. In our study of 163 cases of syphilitic aortic insufficiency, 139 
had positive serologic tests; in 23 cases the tests were negative, but in 19 
of these there was collateral evidence of syphilis. Figures from several sets 
of statistics indicate that from 10 to 15 per cent of patients with syphilitic 
aortic insufficiency will be negative to the usual nonspecific or screening 
serologic tests. It is possible that the incidence might be different with the 
more consistent results of the VDRL tests, but there are no recent statistical 
studies in this respect. However, I do know that the VDRL test may be 
negative in the presence of syphilitic aortic insufficiency, and in several of 
such instances a positive result was obtained with newer antigen-antibody 
reactions, as with the fluorescent antibody technique, for example. 

The possibility of negative serologic tests accompanying an aneurysm 
is the same as that of aortic insufficiency and needs no further comment. 

Treatment 

As one leaves the possibility of certain biologic cure in the treatment 
of acute or infectious syphilis, one enters an area of uncertainty and 
difficulty in evaluation of the effectiveness of treatment of the presumably 
late latent syphilitic who unquestionably has focal disease, whether of 
proliferative or gummatous type. That inflammation and healing with scar 
occurs in aortitis is without question. What the factors are which permit 
the focal activity of the gumma is unknown. It is probably difficult of 
proof that treatment in the late latent stage alters the eventual outcome 
of syphilitic disease in the patient. It is even conceivable that in the case 
of the aorta a therapeutic paradox might hasten morbidity by the resolution 
of inflammation and consequent healing with deforming scar. This is seen 
dramatically upon occasion — the development of rapidly progressing aortic 
regurgitation under treatment. On the other hand, if one refers to the 
incidence of late syphilis as shown in Figure 3, the figures may reflect the 
effect of intensive treatment (in pre-penicillin days) of many patients with 
late latent syphilis who were brought under treatment through case finding. 
Thus, it may be permissible to draw the conclusion that treatment in late 
latency is effective! 

Rosahn,^ however, in analyzing his autopsy material in the light of 
treatment, is not sure how much is gained by treatment. Anatomic lesions 
of syphilis were found in 77 or 38.9 per cent of untreated patients, and he 
points out that only 23.2 per cent of the whole group died primarily as the 
result of syphiUs. (See also paper by Clark and Danbolt in this issue.) He 
arrives at the conclusion that in treated syphilis the case fatality rate is 
about 1 in 5, and indicates that treatment could not have altered the 
course of the disease in more than four out of ten patients, since six out of 
ten died with no evidence of syphilis at autopsy. Actually three out of ten 



696 R. 11. Kampmeier 

with syphilis died of unrelated disease, and he speculates that treatment 
might have affected only two of ten who actually died of syphilis. On the 
other hand, these figures cannot be accepted without thinking in qualifying 
terms of today's population. With the better control of infectious diseases, 
particularly pneumonia and tuberculosis, and advances in surgery which 
permit extension of life, it would seem that the added years might permit 
the development of the fatal lesions of syphilis. (For example, it seems that 
more instances of syphilitic heart disease are recognized among the aged 
today than a couple of decades ago.) Furthermore, if we recognize the 
effectiveness of treatment in syphilis of the central nervous system, particu- 
larly paresis, where we can readily and satisfactorily measure the effect of 
treatment, and also recognize the satisfactory response of the gumma of 
skin or bone to antisyphilitic treatment, one cannot help but draw the 
conclusion that antisyphilitic treatment must have a similar effect upon 
the subcHnical lesions caused by the treponeme. 

Following treatment, however, it must be emphasized that the patient 
be kept under careful observation for some time thereafter. Just as sero- 
and clinical relapse may occur in the patient following the accepted method 
of treatment for infectious syphilis, relapse as shown at times in the spinal 
fluid of the treated paretic, and occasionally in recurrent gummatous 
inflammation indicates that the disease is not necessarily completely 
controlled by accepted standards of antisyphilitic treatment. 



REFERENCES 

1. Kampmeier, R. H.: Comments on the present day management of syphilis. South. 

M. J. 46: 226, 1953. 

2. Clark, E. G. and Danbolt, N.: The Oslo Study of the natural history of untreated 

syphiHs. J. Chronic Dis. 2: 311, 1955. 

3. Rosahn, P. D.: Autopsy Studies in Syphilis: A Monograph. U.S.P.H.S. Publication 

No. 433. U. S. Government Printing Office, Washington, D. C. 6th Printing, 1955. 

4. Kampmeier, R. H.: Skin lesions in early syphilis treated with inadequate doses of 

arsenic. Tr. Am. Clin. Climat. A. 67: 134, 1941. 

5. Francis, H. C. and Kampmeier, R. H.: The bone lesions in acquired tertiary syphilis. 

South. M. J. 36: 556, 1943. 

6. Kampmeier, R. H.: Essentials of Syphilology. Philadelphia, J. B. Lippincott Co., 

1943. 

7. Kampmeier, R. H. and Jones, E.: Esophageal obstruction due to gummata of 

esophagus and diaphragm. Am. J. Med. Sc. 201: 539, 1941. 

8. Morgan, H. J.: Comments on the syphilis problem in the United States. South. 

M. J. 26: 18, 1933. 

9. Moore, J. E. : The Modern Treatment of Syphilis. Springfield, 111., Charles C Thomas, 

1933. 

10. Major, R. H.: Classic Descriptions of Disease. 3rd Ed. Springfield, 111., Charles C 

Thomas, 1945. 

11. Welch, F. J.: Aortic aneurism in the Army and the conditions associated with it. 

Lancet 2: 769, 1875; Editorial, Ibid. 899. 

12. Dohle, E.: tJber Aorten Krankung bei Syphilitischen und deren Bezie hung zur 

Aneurysmenbildung, Arch. klin. Med. 55: 190, 1895. 

13. Reuter, K.: Newe Befunde von Spirochoete pallida in menschlichen Korper undihre 



The Late Manifestations of Syphilis 697 

Bedeutung fiir die Atiologie der Syphilis. Ztschr. f. Hyg. a. Infoktionskr. 51^: 49, 
1906. 

14. Warthin, A. S.: The new pathology of syphilis. Am. J. Syph. 2: 425, 1918. 

15. Weinstein, A., Kampmeier, 11. H. and Harvvood, T. R.: Complete heart block due 

to syphilis. A.M. A. Arch. Int. Med. 100: 90, 1957. 

16. Kampmeier, R. H., Glass, R. M. and Fleming, F. E.: Uncomplicated syphilitic 

aortitis — Can it be diagnosed? Ven. Dis. Inform. 22: 254, 1942. 

17. White, P. D. and Wise, N. B.: Early diagnosis of cardiovascular syphilis. New- 

England J. Med. 217: 988, 1937. 

18. Rich, C. and Webster, B.: The natural history of uncomplicated syphilitic aortitis. 

Am. Heart J. I^3: 321, 1952. 

19. Cochems, K. D. and Kemp, J. E.: Studies in cardiovascular syphilis: III. Effect of 

occupation upon the incidence and type of syphilitic aortitis. Am. J. Syph., 
Conor. & Ven. Dis. 21: 408, 1937. 

20. Kampmeier, R. H. and Combs, S. R.: Prognosis in syphilitic aortic insufficiency. 

An evaluation of factors other than antisyphilitic treatment. Am. J. Syph., 
Conor. & Ven. Dis. 21^: 578, 1940. 

21. Webster, B., Rich, C, Jr., Densen, P. M., Moore, J. E., Nicol, C. S. and Padget, P.: 

Studies in cardiovascular syphilis. III. The natural history of syphilitic aortic 
insufficiency. Am. J. Syph., Conor. & Ven. Dis. 57; 301, 1953. 

22. Kampmeier, R. H.: Saccular aneurysm of the thoracic aorta: A clinical study of 

633 cases. Ann. Int. Med. 12: 624, 1938. 

23. Kampmeier, R. H.: Aneurysm of the abdominal aorta: A study of 73 cases. Am. J. 

M. Sc. 192: 97, 1936. 

24. Zeman, F. D. and Storch, S.: Syphilitic heart disease in the aged. Ann. Int. Med. 

36: 1423, 1952. 

Vanderbilt University School of Medicine 
Nashville, Tennessee 



Some Aspects of Neurosyphilis 



EVAN W. THOMAS, M.D/ 



In the last edition of Sir Jonathan Hutchinson's book, "Syph- 
ilis," published in the early years of this century, we find the statement, 
''It is perhaps not too much to assert that there is scarcely a single type- 
form of disease of the nervous system which has not its representative in 
the chronicles of syphilis."^ This sweeping assertion is justified by the 
chronicles of syphilis recorded in the late nineteenth and early twentieth 
centuries, but it must be modified today and it was probably an exaggera- 
tion in Hutchinson's time for we cannot be sure that neurosyphilis actually 
accounted for all the ills of the nervous system attributed to it in the early 
years of this century. 

It is still true, however, that no single disease has been responsible for 
so many different pathologic reactions in the nervous system as syphilis. 
Hence, neurosyphilis is easily confused with other central nervous system 
diseases, and confirmation of the diagnosis by spinal fluid tests is usually 
necessary. By relying on clinical judgment alone the neurologist, who has 
also had much experience with syphilis, will undoubtedly be right more 
often than wrong in diagnosing symptomatic neurosyphilis, but the greater 
his experience with syphilis, the more he will rely on spinal fluid tests not 
only for the diagnosis but also for determining the activity of the syphilitic 
process. 

While I was at Bellevue Hospital in New York City, patients with 
positive serologic tests for syphilis were sometimes referred to the syphilis 
service for fever therapy because of presumed active neurosyphilis, in spite 
of negative spinal fluid tests for syphilis, i.e., negative complement fixation 
or flocculation tests and normal cell counts. The late Dr. Bernard Dattner, 
an able neurologist, who was in charge of the neurosyphilis cases at 
Bellevue Hospital, was convinced, from his long experience with syphilis 
in Vienna and New York, that active neurosyphilis could not be diagnosed 
in patients who had negative complement fixation tests for syphilis of the 
spinal fluid and normal cell counts. ^ Before I knew Dattner, I was con- 



Read at, Syphilis : A Symposium, Vanderbilt University School of Medicine, Nashville, 

Tennessee, May 17-18, 1963. 
* Consultant to Chicago Board of Health, Chicago, Illinois 

699 



700 Evan W. Thomas 

vinced that I had never seen active neurosyphiUs in patients with negative 
complement fixation and flocculation tests for syphiUs of the spinal fluid, 
but I was by no means certain that the activity of syphilitic processes in 
the central nervous system could be determined by cell counts. This was 
a revolutionary idea in 1937 when Dattner began his work at Bellevue 
Hospital. I was convinced of its validity only after several years of careful 
observations of patients treated for neurosyphilis by fever therapy. The 
first essential in such observations was to make sure that spinal fluid cell 
counts were made as accurately as possible. A technician was specially 
trained for this purpose and great pains were taken to prevent contamina- 
tion of the spinal fluid with red cells when the fluid was collected. 

By the late 1940's Dattner 's ideas had become more or less accepted 
by most physicians working with neurosyphilis in this country, but reports 
of exceptions to the rule were not uncommon. In my own experience, 
exceptions to this rule were very rare and uncertain, but, in a disease like 
syphilis, to claim that exceptions never occurred would be much too 
dogmatic. Exceptions may well have occurred, but unfortunately it was 
usually impossible to prove or disprove them because of the subjective 
factors in evaluating clinical symptoms and the frequent inaccuracy of 
spinal fluid cell counts. The most that Dattner or I could say in such cases 
was that in our experience we seldom, if ever, had satisfactory proof that 
active neurosyphilis could exist with normal cell counts of the spinal fluid. 
To test our belief we gave fever therapy or penicillin to patients suspected 
of having active neurosyphilis, in spite of normal cell counts and (in some 
cases) negative specific tests for syphilis of the spinal fluid, but we were 
never satisfied that these patients benefited from such treatment. Neither 
we nor those who disagreed with us were free from charges of bias, but it 
seemed to Dattner, whose competence as a neurologist was seldom chal- 
lenged, that there was far less opportunity for biased judgment in neuro- 
syphilis when reliance was placed on spinal fluid tests than on clinical 
judgments, provided the laboratory tests were made accurately. Failure to 
diagnose some other disease of the central nervous system in a patient 
known to have syphilis does not necessarily prove neurosyphilis. 

Consequently the early chronicles of neurosyphilis, written before 
spinal fluid tests were known, are inevitably open to question. But, despite 
justifiable skepticism, the early case histories of neurosyphilis cannot be 
rejected out of hand merely because they don't fit contemporary ideas or 
our own experience. Syphilis may have altered more than we realize in the 
course of the past century. Hutchinson, who knew nothing about spinal 
fluid examinations for syphilis, attributed to neurosyphilis a great array of 
disorders of the peripheral nerves and central nervous system. In his book 
we read of headaches, cranial nerve palsies, multiple neuritis of peripheral 
nerves, paraplegias and paralyses, including hemiplegias, occurring often 
in syphilis of from nine months to a few years' duration. ^ We would like 
to know which of these phenomena were caused by early syphilis and 



Some Aspects of Neurosyphilis 701 

which by late syphilis, if indeed they were all syphilitic. Hutchinson does 
not help us answer this question because he was vague about the differ- 
ences between early and late neurosyphilis, even though he was well aware 
of the differences between primary, secondary and tertiary lesions of the 
skin, mucous membranes, bones and organs like the liver. His tertiary 
lesions were chiefly gummas or gummatous reactions which must be 
differentiated from the inflammations and atrophies of neurosyphilis which 
start early in the late stage or not at all and progress very slowly. 

Except for the acute meningitis of secondary syphilis, many of 
Hutchinson's cases of relatively early neurosyphilis, if correctly diagnosed, 
represent a more virulent form of meningovascular syphilis than has been 
reported in more modern textbooks. Probably some of his ' 'spinal paralyses" 
and hemiplegias were actually gummatous reactions involving blood vessels 
and other central nervous system structures. When he tells us that the 
signs and symptoms he describes responded well to mercury therapy, we 
cannot make light of his diagnoses. But therapeutic tests are not always 
reliable proof of diagnoses. For example, we can find in the literature on 
syphilis many contradictory opinions about the effect of heavy metal 
therapy in such phenomena as tabes dorsalis, general paresis and inter- 
stitial keratitis. Hutchinson thought that syphilis predisposed to tabes and 
paresis but did not cause them, yet, somewhat paradoxically, he advised 
mercury for general paresis and maintained that some paretics had imme- 
diate benefit from it.^ We know today that interstitial keratitis and eighth 
nerve deafness associated with congenital syphilis respond well only to 
corticosteroids, yet prior to the advent of the corticosteroids, there were 
many conflicting opinions about the value of treponemacidal agents in 
these conditions. 

However skeptical one may be of the early chronicles of syphilis, I 
think that there can be no doubt that the acute lesions of secondary 
syphilis and the early manifestations of the late stage have become much 
less virulent with the passage of time and this may be especially true of 
neurosyphilis. I think that Dr. Kampmeier, whose many years of service 
in the diagnosis, treatment and control of syphilis we are honoring, will 
agree that the acute meningitis of secondary syphilis has become much less 
severe within his own experience. I am quite certain that it has in mine. 
Unless my memory (without access to old records) misleads me, I saw 
more cases of secondary syphilis with the classical signs of meningitis — 
headache, stiff neck, positive Kernig's sign and palsy of one or more 
cranial nerves— in the 30's than in the 40's when early syphilis was at its 
peak. Since the 40's I have neither seen nor heard of a syphilitic meningitis 
with such pronounced symptoms. 

Whether the late manifestations of neurosyphilis such as primary optic 
atrophy, tabes dorsalis and general paresis would be found in smaller 
percentages of uncured syphilitics now than in the early years of this 
century is impossible to prove one way or the other because penicillin 



702 Evan W. Thomas 

prevents late symptomatic neurosyphilis, as was impossible in the majority 
of clinic patients during the years when prolonged treatment with heavy 
metals was used. So many of the patients treated for late symptomatic 
neurosyphilis at Bellevue Hospital gave histories of previous irregular and 
inadequate treatment with heavy metals^ that I sometimes wondered if 
irregular treatment with small doses of arsenicals, such as 0.3 gm. of 
neoarsphenamine, was not more provocative of symptomatic neurosyphilis 
than suppressive or preventive. Fortunately the opposite of this speculation 
seems to be true of penicillin. Apparently even noncurative doses of 
penicillin are helpful in suppressing or delaying the progress of neurosyphilis. 
Otherwise I think more cases of late symptomatic neurosyphilis would be 
encountered than we have evidence of. 

Rates of first admissions to mental hospitals in the United States 
because of general paresis fell from 6 or slightly over in the 1940's to 0.4 
in 1960, the last year for which I have data.^ The rates may have declined 
still further since 1960, but, with the increased incidence of early infections 
since 1957, we cannot be sure about the future of general paresis. If paretics 
should increase in the future, it will be a sad commentary on our case- 
finding methods because we usually have from 10 to 20 years to find and 
treat the syphilis before mental symptoms develop. 



SPINAL FLUID TESTS FOR SYPHILIS 

Their Function 

Prior to the advent of penicillin, the prevention of symptomatic 
neurosyphilis depended largely on spinal fluid examinations made before 
the onset of symptoms. Fortunately for the patients, this is no longer true 
because asymptomatic neurosyphilis can now be cured, as a rule, by dosages 
of penicillin that are used for late latent cases. No doubt the perfectionist 
would always like to know if asymptomatic neurosyphilis is present, but 
unless one is prepared to do follow-up spinal fluid examinations every six 
months for at least two years after treatment of asymptomatic neuro- 
syphilis, one will have not only fallen short of the perfectionist goal but 
also have failed to benefit the patient in any way. Therefore, unless one is 
engaged in a research project and is prepared to take personal responsibility 
for spinal fluid cell counts, I think routine spinal fluid examinations of late 
asymptomatic syphilitics should be discouraged. Even when asymptomatic 
neurosyphilis is present, the risk of progression to symptoms after a patient 
has received 4.8 million units of repository penicillin^ is so slight that in 
my opinion it does not justify the inconvenience to the patient of lumbar 
taps every six months for at least two years. 

But, as previously mentioned, spinal fluid examinations are of crucial 
importance in differentiating symptomatic neurosyphilis from other diseases 



Some Aspects of Neurosyphilis 703 

of the central nervous system. For this reason, at the risk of boring those 
who are familiar with the tests, some detailed information about the tests 
must be given for those who have had little experience with them. 

Types 

Specific Tests. Biologic false positive tests for syphilis of the spinal 
fluid with lipid antigens are rarely, if ever, encountered. Consequently, 
positive conventional tests for syphilitic reagin in the spinal fluid are 
reliable evidence of past or present neurosyphilis. Following successful 
treatment of neurosyphilis, quantitative positive specific tests usually 
decline gradually but, as a rule, remain positive for some years. 

Cell Counts. When associated with positive spinal fluid specific tests 
for syphilis, increased cell counts of more than 4 per cu. mm. indicate an 
active syphilitic process in the central nervous system. Following treatment 
of active cases, the cell counts should become normal within six months. 
Relapses are indicated by a renewed pleocytosis. Lymphocytes, plasma 
cells and other mononuclear cells will usually remain intact for 24 hours in 
sterile spinal fluid kept in an icebox, but, since the cells disintegrate quite 
rapidly at room temperatures, the sooner cell counts are made after the 
fluid is drawn, the better. Before making counts, the fluid should always 
be well shaken to dislodge cells from the sides of the tube or container. 
Red cells inevitably interfere with counts of lymphocytes in the spinal 
fluid when one is concerned with low counts of 4 or more per cu. mm. 
Therefore, every effort should be made to avoid contamination of the 
fluid with red cells when the fluid is drawn. 

Total Protein Tests. The normal range of total protein in the spinal 
fluid, as determined by the tests usually used, is from 20 to 40 mg. per 
100 ml. Individuals differ in the quantities that are normal for them. Active 
neurosyphilis is frequently associated with increased total protein but 
abnormally high values may persist for from one to two years after success- 
ful treatment for neurosyphilis. 

Colloidal Gold Tests. These tests are not a reliable guide to the activity 
of neurosyphilis. First zone curves indicate parenchymatous damage. They 
are usually found in cases of general paresis and multiple sclerosis. Abnormal 
curves usually persist for at least several years after successful treatment 
of neurosyphilis and they are not influenced by retreatment. 



TREATMENT OF NEUROSYPHILIS 

PeniciUin is the treatment of choice for all types of neurosyphilis. 
According to the reports of Hahn and co-authors on the results of treatment 
of asymptomatic neurosyphilis^ and general paresis^ in 12 co-operating 
medical centers, 6 million units of repository penicillin are probably ample 
for general paresis as well as asymptomatic neurosyphilis. This treatment 



704 Evan W. Thomas 

is preferably given by injections of 1.2 million units of procaine penicillin 
in oil and aluminum monostearate (PAM) every three or four days for 
five injections. 

It would be of value to know the minimal effective dose of penicillin 
for neurosyphilis but there is little or no likelihood that this can be deter- 
mined in the near future. I suspect that a single treatment with 2.4 million 
units of benzathine penicillin would provide ample treatment for most 
cases. There is no reason, so far as I can determine, why neurosyphilis 
should require more treatment or larger doses of penicillin than secondary 
syphilis, but I have no data to confirm this suspicion and unless one can 
obtain a two-year follow-up with spinal fluid examinations on a repre- 
sentative series of cases, there is no point in trying minimal doses. 

Treatment with penicillin unquestionably causes healing of the syph- 
ilitic processes in the central nervous system, but healing of late lesions 
occurs with scar tissue and it is impossible to restore normal function when 
irreparable damage has occurred to important tissues. Patients treated for 
general paresis may improve dramatically after penicillin, but they do not 
have the same powers of concentration as before the paresis developed and 
some require custodial care for the rest of their lives. In our experience at 
Bellevue Hospital, if paretics failed to improve promptly following treat- 
ment with penicillin, further treatment with higher dosages was ineffec- 
tively 

In penicillin-sensitive cases, erythromycin is now advised as the most 
effective and practical substitute for penicillin. Based on experience in the 
treatment of early syphilis," erythromycin given orally in 500 mg. doses 
four times a day at four or five-hour intervals for 10 to 15 days should be 
ample treatment for all forms of neurosyphilis. General paresis was treated 
successfully at Mayo Clinic with 750 mg. of chlortetracycline four times a 
day for 15 days, but few patients will tolerate such prolonged treatment 
with high doses of this antibiotic without gastrointestinal symptoms. ^^ 



CONCLUSION 

Although all types of neurosyphilis can now be completely arrested or 
cured with penicillin, the goal we need to keep in mind is the prevention 
of symptomatic cases. This goal is on the way toward attainment and it 
should be attained in the near future, if all medical facilities are alert in 
discovering syphilis before late symptoms develop. 

Much of the glamor formerly associated with the diagnosis and treat- 
ment of neurosyphilis is now gone and, in preparing this paper, I have been 
conscious chiefly of reminiscing. There have been moments when I have 
been tempted to relegate neurosyphilis to the limbo of medical history, but, 
lest we yield to this temptation, it is well to remember that our ignorance 
of the underlying mechanisms responsible for the hypersensitive reactions 



Some Aspects of Neurosyphilis 705 

observed in neurosyphilis is profound. Obviously the T. pallidum is a 
sophisticated organism which learned long ago to take advantage of weak- 
nesses and errors in the long evolution of immune mechanisms in man. 
How little we understand these immune mechanisms is shown by our 
failure to explain them in neurosyphilis. It is notable that modern textbooks 
on immunology avoid discussing syphilis apart from the laboratory tests 
used as aids to diagnosis. Yet no other single disease presents so great a 
challenge to immunology. How the body decreases demonstrable trepo- 
nemes to such small numbers in all late lesions except the meningo- 
encephalitis of general paresis is still unknown. Nor do we know why 
some central nervous system tissues react with inflammations and others 
only with degenerative lesions. These are important questions for immu- 
nology and until we are able to answer them we can ill afford to forget 
neurosyphilis. 



REFERENCES 

1. Hutchinson, Sir Jonathan: Syphilis, new ed. Funk & Wagnalls Co., 1913, p. 273. 

2. Dattner, B., Thomas, E. W. and deMello, L.: Criteria for management of neuro- 

syphilis. Am. J. Med. 10: 463 (April) 1951. 

3. Hutchinson, Sir Jonathan: Syphilis, new ed., pp. 273-303. 

4. Ibid., pp. 310-311. 

5. Thomas, E. W.: Blood and spinal fluid tests for reagin before and after treatment 

of neurosyphilis. J.A.M.A. 143: 718 (Oct. 24) 1953. 

6. VD Fact Sheet, 1962. Public Health Service, Communicable Disease Center, 

Atlanta 22, Ga. 

7. Hahn, R. D. and others: Penicillin treatment of asymptomatic central nervous 

system syphilis: Probability of progression to symptomatic neurosyphilis. A.M. A. 
Archiv. Dermat. 74: 355 (Oct.) 1956. 

8. Hahn, R. D. and others: Penicillin treatment of asymptomatic central nervous 

system syphilis; results of therapy as measured by laboratory findings. A.M. A. 
Arch. Dermat. 74: 367 (Oct.) 1956. 

9. Hahn, R. D. and others: The results of treatment in 1,086 general paralytics the 

majority of whom were followed for more than five years. J. Chronic Dis. 7: 209 
(March) 1958. 

10. Dattner, B., Thomas, E. W. and deMello, L.: Treatment of neurosyphilis. J.A.M.A. 

141: 1260 (Dec. 24) 1949. 

11. Moore, M. B., Vanderstoep, E. M., Knox, J. M. and Montgomery, C. H.: Oral 

erythromycin in the treatment of early syphilis. J. Invest. Dermat. 38: 285 (May) 
1962. 

12. Kierland, R. R. and O'Leary, P. A.: Oral treatment of neurosyphilis with Aureo- 

mycin. Am. J. Syph. 34: 443 (Sept.) 1950. 

500 North Dearborn Street 
Chicago 10, Illinois 



ff 



Prenatal Syphilis 

ARTHUR C. CURTIS, M.D.* 
OSGOODE S. PHILPOTT, JR., M.D.** 



The incidence of prenatal syphilis has continued to decline over 
the past 20 years. There were 4085 cases of prenatal syphilis reported in 
1962, of which the great majority were in adults who were born with the 
disease. Only 330 members of this group were children of one year of age 
or less. This, however, is very alarming because there has been a gradual 
increase in prenatal syphilis in this age group since 1957. The 1962 total 
for children under one year of age represents a 100 per cent-plus increase 
over the 1957 total for the same group. Attention should be drawn to these 
patients, because prenatal syphilis, an entirely preventable disease, should 
not occur with proper prenatal care. 

Prenatal syphilis is syphilis transmitted to the fetus in utero by the 
mother. The infection occurs through the placenta, and it seldom, if ever, 
takes place before the fourth month of gestation. Spirochetes are not found 
in fetal tissue prior to 18 weeks of intrauterine life. It has been suggested, 
and we concur, that a barrier to the passage of the Treponema pallidum is 
created by the well developed Langhans layer of the chorion.^ After the 
sixteenth week, this layer is not found in the placenta, and fetal infection 
may ensue. Thus, adequate treatment of the pregnant mother prior to the 
fourth lunar month of her pregnancy will prevent congenital infection. 
Adequate treatment of the mother after 18 weeks of gestation will bring 
about a cure in utero if infection has occurred ; however, treatment cannot 
prevent possible osseous stigmata. Also, one cannot predict the later occur- 
rence of Glutton's joints, neural deafness, or interstitial keratitis following 
adequate antiluetic treatment. It is of interest that the Treponema pallidum 
has not been identified in these lesions by most workers, and thus they 
may represent phenomena of hypersensitivity. 

Spirochetemia may result in fetal wastage or neonatal death. Thomas'* 
states that 25 per cent of fetuses infected in utero in untreated cases die 



* Professor and Chariman, Department of Dermatology, University of Michigan Medical 

School, Ann Arbor 
** Department of Dermatology, University of Michigan Medical School 

707 



708 Arthur C. Curtis, Osgoode S. Philpott, Jr. 

before birth. Another 25 to 30 per cent will die shortly after birth if un- 
treated. Of all those infected, untreated children who survive infancy, 40 
per cent develop late symptomatic syphilis. 

With regard to twins, identical (single ovum) twins are both infected 
or neither one is infected. However, with nonidentical (double ova) twins, 
infection of one and not the other has been reported.^ This is easily explained 
by the presence of two placentas, one for each child. 

Another interesting phenomenon is the event of third generation 
syphilis. Although several cases have been reported and appear to be 
authentic, the authors are hesitant to accept such an occurrence. Third 
generation syphilis may perhaps exist, but more likely it represents mater- 
nal reinfection. Dr. Udo Wile has a photograph of a young Negro woman 
with a chancre on her lower lip and classical Hutchinsonian upper central 
incisors. 



CLINICAL MANIFESTATIONS 

The clinical manifestations of prenatal syphilis include early lesions, 
late lesions, and stigmata which are the results of scarring. 

Early Manifestations (Figs. 1-6) 

Active signs and symptoms at birth denote a serious prognosis. Usually 
the infant appears well at birth, and the early lesions are not observed 
until the second to sixth week postpartum. Occasionally, a year or two may 
pass before the early signs are manifest. The early clinical lesions are those 
of secondary syphilis; however, they are more severe than the acquired 
secondary lesions in the adult. In general appearance the infant usually 
has a well-formed body that may be slightly underweight. The "classic" 
picture of marasmus, pot belly, withered skin, old man facies and pseudo- 
paralysis of Parrot is most often seen in premature infants and associated 
with severe infection. 

The early cutaneous lesions resemble those of acquired secondary 
lesions. Their distribution is a significant feature, and involvement includes 
the circumoral region, palms, soles and anogenital area. Vesicular or bullous 
involvement of the palms and/or soles is somewhat uncommon, but highly 
diagnostic. Annular lesions may be striking; however, ulcerative lesions are 
rare. Kampmeier noted cutaneous lesions in 52 per cent of patients under j 
the age of six months.^ Darkfield examinations are usually positive. 

More common than skin eruptions are lesions of the mucous membranes 
and mucocutaneous areas. Rhinitis causing snuffles is a common finding and 
often is the first clinical manifestation of prenatal syphilis. The nasal 
discharge may be hemorrhagic, and it is always very infectious. In addition 
to involvement of the mouth, throat and nose, fissures may occur about 
the lips or perianally. The scarring which results from healing forms 



Prenatal Syphilis 



709 




\ 



i^ 



Figure 1. Marasmic infant showing snuffles and perioral lesions.* 

Figure 2. Syphilitic infant with "pot belly" and annular cutaneous lesions. 
These children often have a hepatosplenomegaly. 

Figure 3. Cutaneous manifestations of prenatal syphilis involving perineal area. 

Figure 4. Papulosquamous eruption of prenatal syphilis with snuffles. Note the 
annular characteristics of some lesions. 



* Figures 1 through 7 by courtesy the Department of Pediatrics, 
University School of Medicine. 



Vanderbilt 



710 



Arthur C. Curtis, Osgoode S. Philpott, Jr. 




Figure 5. Syphilitic bullous 
eruption of face, with annular 
lesions of forehead and split 
papules at corners of mouth. 



y 





Figure 6. 
on hand. 



Cutaneous lesions of face secondary to snuffles. Note rupial lesions 



rhagades. In addition to these lesions, condylomata lata are occasionally 
observed. 

While snuffles is an early clinical finding, the most common early 
manifestations involve the bones and joints. The long bones are usually 
involved, and the most common lesion is osteochondritis. Characteristic of 
this lesion is the ''saw-tooth" metaphysis seen in the roentgenogram. The 
intense pain and tenderness of osteochondritis underlie the pseudoparalysis 
of Parrot. An associated feature is periostitis which is also painful when 



Prenatal Syphilis 



711 



acute. In later life this can account for blunting of the scapular spines and 
anterior tibeal margins. Rarely a form of osteitis of the phalanges can lead 
to syphilitic dactylitis, which is seen during the first two years of life. 
Usually the radiological changes of osteochondritis seen in the ends of the 
long bones are gone by the eighth month. However, periostitis can be 
observed during the entire last half of the first year of life. 

Hepatosplenomegaly is a frequent finding clinically. Kampmeier^ noted 
a 64 per cent incidence, which was the most frequent clinical finding in his 
group of cases. Reports of jaundice and edema secondary to hepatic 
involvement are recorded. 

Meningitis occurs in 40 to 50 per cent of babies born with prenatal 
syphilis. The involvement may be asymptomatic, and the diagnosis is 
dependent upon spinal fluid examination. 

Other findings associated with early syphilis include: anemia, saddle 
nose, pneumonia alba, generalized lymphadenopathy, peritonitis, nephrotic 
syndrome,^ iritis, and choroiditis. (Chorioretinitis is a late manifestation in 
prenatal lues.) 

Late Disease (Figs. 7, 8) 

The late lesions of prenatal syphilis correspond to the tertiary lesions 
of acquired syphilis. Generally, the lesions develop after two years of age, 
and seldom occur past the age of 30 years. 

Interstitial keratitis occurs in 30 to 50 per cent of cases. It may rarely 
be seen in acquired syphilis.^ The lesion consists of vascularization of the 
cornea with precipitation of cells and pigment on the posterior surface of 
the cornea. The lesion is more common in females, and frequently is seen 
during the early teens. Ulceration is rare, and the process is usually accom- 
panied by photophobia. The majority of episodes involve both eyes, 
although the phenomena may present initially in just one eye. Untreated, 





Figure 7. Interstitial keratitis due to prenatal syphilis. (Kampmeier: Physical 
Examination in Health and Disease. Courtesy F. A. Davis Co.) 



712 Arthur C. Curtis, Osgoode S. Philpott, Jr. 



/ 




Figure 8. Glutton's joints. 



a course of 12 to 18 months may be expected. The lesions do not respond 
to antihietic treatment. The treatment of choice is topical steroids. 
Ashworth^ reports on the five-year follow-up of 50 cases, and states that 
the treatment is effective. The expectation of visual acuity after treatment 
is good. There is little or no corneal scarring, and the presence of corneal 
vascularization in early cases had no ill effect on the good prognosis. It is 
interesting that Putkonen^ found no interstitial keratitis in his 36 patients 
who received adequate early antisyphilitic treatment. In the event of 
inadequate treatment and late leukomatous scarring of the cornea, corneal 
transplantation can be utilized to restore vision. Owens'^" series showed 
that approximately half of the grafts remained clear. Other eye lesions are 
seen occasionally with interstitial keratitis, and these include iritis and 
iridocyclitis early and glaucoma late. 

Neurosyphilis is probably the second most common lesion of late 
congenital syphilis. The diagnosis depends upon spinal fluid examination. 
The diagnosis is usually established during the teens, but may be seen 
after the fifth year of life. As is true in the acquired forms also, the lesion 
is more common in the white race. The overall incidence in the white race 
is approximately 12 per cent, as compared to approximately 3 per cent in 
Negroes. The various clinical manifestations of acquired neurosyphilis are 
seen in children but there is seldom sharply defined tabes or paresis. Less 
than 1 per cent will develop paresis. The poor prognosis of neural syphilis 
prior to penicillin treatment is no longer tenable. The prognosis with 
adequate treatment is very good. 

A very late manifestation of prenatal syphilis is the uncommon occur- 
rence of neural deafness. Generally, neural deafness is accompanied by a 
normal spinal fluid examination. The prognosis in untreated cases is poor. 
Even with antiluetic treatment, the deafness is relentlessly progressive. 
The deafness usually does not develop before adult life, and it may be 






Prenatal Syphilis 7I3 

associated with findings of dizziness, vertigo and tinnitus. Hahn, Rodin 
and Haskins" have recently reported the use of steroids in the treatment 
of neural deafness with good results. They found improvement in 10 of 19 
patients with treatment. Usually patients are better within two weeks; 
however, the authors recommended a month's trial of therapy. Morton^^ 
has shown that radiological study of the petrous temporal bone in this 
disorder is negative. 

The development of gummas and gummatous inflammations in con- 
genital lues is similar to that of acquired syphilis. 

Clutton^^ described bilateral hydrarthrosis (Glutton's joints) in 1886. 
This is a syphilitic synovitis without involvement of bone or cartilage. It 
affects the knees most commonly, and is usually bilateral. It occurs gen- 
erally between the ages of 8 and 15 years. It begins acutely or subacutely, 
and resolves spontaneously without residual joint damage within several 
months. The clinical picture includes fever, and contrary to Glutton's 
original description, the joints may be red, warm and painful. The lesions 
respond to steroids, but not to penicillin or salicylates. Borella, Goodbar 
and Glark'' have described eight cases recently, and point out the need for 
accurate diagnosis so that harmful treatment will not be given. As indicated 
by them, the major diseases to be ruled out include pyogenic arthritis. 
Still's disease, sickle disease, lupus erythematosus and acute rheumatic 
fever. 

The association of arthritis with congenital syphilis has been reviewed 
by Gray and Philp.^^ They point out that arthritis occurs in two forms 
with congenital syphilis, and a third form common to both congenital 
syphilis and acquired syphilis. Osteochondritis appears in infants, while 
Glutton's joints are the more common manifestation in older children. 
The third form is similar to the arthritis of acquired tertiary syphilis of 
adults. This form may be synovial or osseous. The synovial form is seen 
in children and is actually a perisynovitis. The osseous form begins as an 
epiphysitis and eventually involves all the structures of the joint. This 
chondro-osteoarthritis is the rare von Gies joint, and may lead to ankylosis. 
Radiologically, involvement of the articular cartilage may be recognized 
by diminution in the joint space. Bone erosion may appear within the 
involved joint, and is seen centrally. The marginal types of erosion seen 
with tuberculosis have not been described in congenital syphilitic arthritis. ^^ 
The earlier the diagnosis and treatment, the better is the prognosis. 

, It is of interest to note that the juxta-articular nodules which rarely 
occur in acquired syphilis apparently do not occur at all in prenatal syphilis. 

It was once the feeling that prenatal lues tended to spare the cardio- 
vascular system. More recently, however, there have been many reports 
which make such an observation doubtful. Bonugli^^ has described a series 
of 15 cases in which there is good evidence that patients with prenatal 
syphilis do develop aortic and aortic valvular lesions. The involvement 
occurs at various ages, but is extremely rare. 



714 



Arthur C. Curtis, Osgoode S. Philpott, Jr. 



Stigmata (Figs. 9-13) 

Some of the lesions of prenatal lues produce scars which persist as 
stigmata of the disease. Many of these findings occur on or about the face. 
The saddle nose resulting from rhinitis and/or destructive osseous changes 
is one of them. Also significant is the nasal septal perforation occasionally 
encountered. Luetic involvement of the skull in infancy may produce bony 
overgrowth and the resultant frontal bosses. The maxilla and mandible may 
be similarly involved. The destructive cutaneous lesions about the lips and 
cheeks may scar, to produce rhagades. While not so obvious, another 
stigma is the lesion of choroiditis. 

The most pathognomonic sign of prenatal lues is the presence of 
Hutchinsonian upper central incisors. Putkonen^^ found an incidence of 
44.7 per cent in his series of 254 patients with prenatal syphilis. He stresses 
the importance of the shape of these permanent teeth. They are barrel- 
shaped or show a convergence of both lateral margins toward the cutting 
edge. The crescentic notch of the cutting edge is only of diagnostic value 
when covered by enamel. Syphilitic involvement of the first molar, so-called 
bud molar or Moon molar, was present in 22 per cent of these cases. 
Putkonen and Paatero^^ have also demonstrated that x-ray study of the 
unerupted central incisors, after one year of age, can reliably detect 
Hutchinsonian formation. Such examination is not reliable for first molars. 
One of the most interesting recent findings regarding syphilitic dental 
changes is their prevention by early treatment. Putkonen^ has presented 
51 cases of prenatal syphilis adequately treated during the latter half of 
pregnancy or during the first three months of life. In none of these patients 
did dental changes due to syphilis occur. Such changes did occur, however, 
in 7 of 15 cases treated during the fourth month of neonatal life or later. 




Figure 9. Characteristic syphilitic facies with involvement of the supporting 
tissues of the nose with mouth breathing. 



Prenatal Syphilis 



715 



Figure 10. Syphilitic facies in an adult 
showing prominent frontal bossae, nasal in- 
volvement, rhagades and prognathous chin. 



i^" 

f 




Fig. 11 Fig. 12 

Figure 11. Syphilitic dental changes of incisors and involvement of the first 



molars. 



Figure 12. Hutchinsonian upper central incisors. 



716 



Arthur C. Curtis, Osgoode S. Philpott, Jr. 




Figure 13. Saber shins. 



It was also suggested that such early treatment protects against interstitial 
keratitis. 

The classic Hutchinson^ s triad of interstitial keratitis, neural deafness, 
and upper central incisor involvement is actually quite rare. 

The development of saber-shin appears after previous tibial osteitis. 
Another bone which is located near the surface, the clavicle, also acts as a 
diagnostic landmark. Unilateral thickening of the inner third of the 
clavicle constitutes the uncommon sign of Higoumenakis. A lesser diagnostic 
aid is the presence of a Graves^ scaphoid scapula. 

Autoimmune Phenomenon 

An interesting phenomenon, not necessarily associated with prenatal 
syphilis, is paroxysmal cold hemoglobinuria (PCH). The clinical signs include 
muscular cramping, headache, hyperpyrexia and hemoglobinuria, which 
usually clears within 24 hours. Urticaria and acrocyanosis may also be 
present, as well as transient splenomegaly and jaundice. The typical onset 
is precipitated by exposure to cold and occurs within minutes or several 
hours. The paroxysms are reportedly decreased or possibly eliminated by 
adequate antiluetic treatment. A study of two interesting cases has 
recently been presented in the literature by Weintraub et al.^^ This work 
describes the Donath-Landsteiner antibody as a biphasic hemolysin of 
variable thermolability. In most cases the biphasic hemolysin is not inac- 
tivated by 30 minutes at a temperature of 56° C. It requires a temperature 



Prenatal Syphilis 717 

below 15-20° C. to bring about fixation of the antibody on erythrocytes. 
Complement is not necessary for this fixation; however, hemolysis upon 
rewarming to 37° C. will not occur in the absence of complement. The 
optimum serum pH for Donath-Landsteiner antibodies is in the range of 
7.0 to 8.0, whereas, the optimal range for cold hemagglutinins is 6.5 to 6.8. 
Syphilitic infection may damage or alter erythrocytes in such a way as to 
make them antigenic. The resultant antibody formation would thus con- 
stitute PCH as an autoimmune phenomenon. Because the erythrocyte in 
paroxysmal nocturnal hemoglobinuria is faulty in stromal lipids, Weintraub 
et al. studied the erythrocyte of PCH in this aspect. They found no such 
lipid abnormality in the one case examined. The Coombs' test was found 
to be positive in one patient studied by Parish and Mitchell. ^'^ 



LABORATORY INVESTIGATION 

A darkfield examination of the umbilical vein at delivery will be posi- 
tive in more than half of the cases of congenital syphilis. 

The serological examination of the patient with prenatal syphilis can 
be complicated by passively transferred serum factors and biologic false 
positivity. Over all, the cord blood obtained at delivery is of very little 
value because it often reflects passively transferred antibodies. It is occa- 
sionally of value if the titer is markedly greater than that of the mother. 
An excellent discussion of neonatal serology was presented by Rein and 
Reyn^i a few years ago. The following discussion reflects their thoughts on 
the subject. 

A seropositive pregnant woman should be investigated to determine 
whether she has syphilis or has a biologic false positive reaction in her 
serum. If one is not able to do this, the patient should be treated to protect 
the fetus. After birth, the child should be followed with serial quantitative 
serological tests for six months. 

A negative serological test in a neonate does not exclude prenatal 
syphilis, since a fetus infected late in gestation may develop positive 
serological tests at variable times from birth. 

The half-life of passively transferred reagin is approximately 32 days. 
Thus, there is a 50 per cent reduction in quantitative titers after 32 days 
from birth. Passively transferred reagin will not cause positive serologic 
tests for syphilis after three months postpartum. Passively transferred 
antibodies will not cause positive specific treponemal antigen tests for 
syphilis after six months postpartum. 

The frequency and degree of seropositivity in infants depends upon 
several factors. The higher the mother's titer at delivery, the greater is the 
likelihood of neonate titer, and the longer will it be necessary to attain 
seronegativity. The frequency of neonatal reactors is increased by more 
sensitive serological tests. The type of test used is important. Passively 



718 Arthur C. Curtis, Osgoode S. Philpott, Jr. 

transferred maternal reagin in the infant's serum is more readily detected 
by complement fixation than by flocculation techniques. Similar titers are 
found in the mother and child with complement fixation tests, while 
flocculation tests record minimal amounts of reagin in the child's blood as 
compared to that of the mother. Thus, there are two antibodies: the 
complement fixation antibody which may pass through the placenta, and 
the flocculation antibody, which may not. 

The levels of immobilizing antibodies are comparable in the mother 
and child. In the study of 30 infants by Austin and Nelson, as quoted by 
Rein and Reyn, the passive transfer of immobilizing antibodies was found 
in all instances. The time for disappearance from the serum depended upon 
the amount transfered. The Fluorescent Treponemal Antibody (FTA) test 
is positive earlier than the Treponema Pallidum Immobilization (T.P.I.) 
test in primary acquired syphilis; however, Vignali^^ found that in con- 
genital syphilis both tests give the same results. Cailland and Meinicke^^ 
studied the results of the T.P.I, test in 19 severe cases of lues connata 
recens and on 12 children with passively transferred antibodies. The results 
were those of ''classical serological reactions." The test is a useful guide to 
the results of early treatment. In 35 of the 36 cases treated by Putkonen,^ the 
T.P.I, reverted to negative, while in the thirty-sixth case it was equivocal. 

Passive transfer of antibodies causing false serologic tests and/or 
T.P.I, tests in children were found in 66 per cent of the cases described by 
Miller et al.^''. In his series of 400 children, he found a rate of 11 per cent 
biologic false positives after passive transfer could be eliminated as a cause. 
This is lower than the rate of 40 per cent false positive sera found in adults. 
In addition, children do not show the preponderance of females with 
regard to biologic false positivity. The incidence of systemic disease in 
young children associated with true biologic false positivity is not high.^^ 



TREATMENT 

The treatment of prenatal syphilis is aqueous procaine penicillin G, 
50,000 units per pound of body weight. This total dose is divided by ten 
and given as daily intramuscular injections. 

The neonate should be followed with quantitative STS every month 
for six months, then every third month for one year. Ninety per cent of 
these cases treated adequately and early will be seronegative within one 
year. If the patient is two years or older when first treated, the serology 
may never become negative. Spinal fluid examinations should be done 
whenever clinical suspicion of neural syphilis is present. As a general rule, 
the febrile Herxheimer reaction at the start of penicillin therapy is to be 
expected when the clinical signs of active prenatal syphilis are present. 

Prenatal syphilis can be totally prevented by frequent prenatal exami- 
nations, proper diagnosis, and adequate treatment of the infected mother. 



Prenatal Syphilis 719 

REFERENCES 

1. Kampmeier, R. H.: Essentials of Syphilology. Philadelphia, J. B. Lippincott Co., 

1943. 

2. Moore, J. E.: The Modern Treatment of Syphilis. 2nd Ed. Springfield, 111., Charles C 

Thomas, 1944. 

3. Stokes, J. H., Beerman, H. and Ingraham, N. R.: Modern Clinical Syphilology. 

3rd Ed. Philadelphia, W. B. Saunders Co., 1944. 

4. Thomas, E. W.: Syphilis: Its Course and Management. New York, Macmillan Co., 

1949. 

5. Hutchinson, J.: Syphilis. W. T. Keener & Co., 1905. 

6. Brown, J. J. and Moore, M. B.: Congenital syphilis in the United States. Clin. 

Pediat. 2: 220, 1963. 

7. Papaioannou, H. C, and others: Pediatrics 27: 635, 1961. 

8. Ashworth, A. N. : Results of local cortisone therapy in syphilitic interstitia 1 keratitis. 

Brit. J. Vener. Dis. 2J^: 83, 1958. 

9. Putkonen, T.: Does early treatment prevent dental changes in congenital syphilis? 

Acta dermatovener. 1^2: 240, 1963. 

10. Owens, W. C. and others: Symposium: Corneal Transplantation. V. Results. Am. J. 

Ophth. 21: 1934, 1948. 

11. Hahn, R. D., Roden, P. and Haskins, H. L.: Treatment of neural deafness with 

prednisone. J. Chronic Dis. 15: 395, 1962. 

12. Morton, R. S.: Radiology in late congenital syphilis nerve deafness. Brit. J. Vener. 

Dis. 38: 162, 1956. 

13. Clutton, H. H. : Symmetrical synovitis of the knee in hereditary syphilis. Lancet 1: 

391, 1886. 

14. Borella, L., Goodbar, J. E. and Clark, G. M.: Synovitis of the knee joints in late 

congenital syphilis. J.A.M.A. 180: 190, 1962. 

15. Gray, M. S. and Philp, T. : Syphilitic arthritis. Ann. Rheum. Dis. 22: 19, 1963. 

16. Bonugli, F. S.: Involvement of the aortic valve and ascending aorta in congenital 

syphilis— a review. Brit. J. Vener. Dis. 37: 257, 1961. 

17. Putkonen, T.: Dental changes in congenital syphilis. Acta dermatovener. 1^2: 44, 

1962. 

18. Putkonen, T. and Paatero: X-ray photography of unerupted permanent teeth in 

congenital syphilis. Brit. J. Vener. Dis. 37: 190, 1963. 

19. Weintraub, A. M., Pierce, L. E., Donovan, W. T. and Rath, C. E. : Paroxysmal 

cold hemoglobinuria. Arch. Int. Med. 109: 589, 1962. 

20. Parish, D. J. and Mitchell, J. R. : Syphilitic paroxysmal cold hemoglobinuria. J. 

Clin. Path. 13: 237, 1960. 

21. Rein, C. R. and Reyn, A.: Serology of treponematoses. Bull. World Health Org. 11^: 

193, 1956. 

22. Vignali, C: Esame comparativo fra test di immobilizzazione (TPI) e test di 

fluorescenza (FTA) nel sero siero di luetici in varie condizioni cliniche. Gior. ital. 
derm at. e sif. (Milan) 103: 35, 1962. 

23. Cailland and Meinicke, K.: Das Verhalten des Nelson Tests bei kehandelter Lues 

connata recens. Miinchen med. Wchnschr. 102: 1737, 1960. 

24. Miller, J. L. and others : A study of the biologic falsely positive reactions for syphilis 

in children. J. Pediat. 57: 548, 1960. 

University Hospital 
Ann Arbor, Michigan 



Worldwide Problems in the Diagnosis 
of Syphilis and Other Treponematoses 

JOHN C. HUME, M.D., Dr.P.H.* 



The broad title given this paper makes advisable a prefatory 
definition of its subject matter. There is here a review of the etiology and 
natural history of the treponematoses. Brief consideration is also given to 
some of the experimental workf which has a bearing on the diagnosis of 
this group of diseases. Finally, some of the specific problems in diagnosis 
which are of importance and general interest are discussed. No effort is 
made to cover the literature in extenso and certain diagnostic problems of 
major importance such as biologic false positive serologic tests and the 
whole subject of serodiagnosis are arbitrarily omitted. The major emphasis 
is on the interrelation of diagnostic and public health problems. 



THE TREPONEMATOSES: A REVIEW OF THE ETIOLOGY, 
INTERRELATIONSHIPS, NATURAL HISTORY AND EPIDEMIOLOGY 

In Table 1, information regarding venereal syphilis, endemic syphilis, 
yaws and pinta is presented which summarizes our knowledge regarding 
the etiologic agent, the clinical course in man, and certain aspects of the 
epidemiology of each disease. In this table and elsewhere in the paper, the 
term "endemic syphilis" includes those manifestations of treponemal dis- 
ease referred to by such words as bejel, dichuchwa and njovera in various 
areas of the world. 

It will be noted in section 1 of the table, dealing with the etiologic 
agent, that while different names are ascribed to the treponemes of syphilis, 
yaws and bejel (pallidum, pertenue and carateum respectively), the demon- 
strable differences among them are limited to their behavior in animals, 
are quantitative rather than qualitative and are neither constant nor 
definitive. Given a strain of treponeme, the source of which is unknown. 



* Professor of Public Health Administration, The Johns Hopkins University, Balti- 
more, Maryland 



t Specific references to the experimental work mentioned in this discussion are not 
given. They can be located in the work of Turner and Hollander.^ 

721 



722 John C. Hume 

it is impossible incontrovertibly to establish, with techniques currently 
available, that its origin was a case of venereal syphilis, endemic syphilis, 
yaws or pinta. In fact, some strains from cases of human yaws, which 
produce lesions in rabbits considered to be typical of yaws, have after 
several passages through rabbits come to produce lesions considered to be 
typical of venereal syphilis. The reverse trend has not been noted. 

In reviewing the clinical information as shown in section 2 of the 
table, one is struck again by the similarities among the various manifesta- 
tions of treponemal disease. They all have initial lesions followed b}^ more 
extensive ''secondary" manifestations and all exhibit the phenomenon of 
latency. The major difference is in the types of tissue involved in the late 
stages. Even in terms of response to therapy, the differences are quantita- 
tive. In general, it may be said that venereal syphilis is the most protean 
in its manifestations and that virtually any lesion produced by the other 
three entities may be produced by it. The spectrum of pathologic response 
seems to narrow as one considers in order endemic syphilis, yaws and 
pinta. Similarly, generalizations regarding response to therapy can be made. 
For example, more treatment is possibly required to effect a cure in venereal 
syphilis than endemic syphilis and certainly less is required for yaws than 
for syphilis. While the clinical response of skin lesions of pinta to treatment 
is apparently slower than for syphilis or yaws, the amount of treatment 
required to effect the response is presumably no greater than for yaws. 

It is in section 3 of the table dealing with epidemiologic information 
that the major differences among these diseases appears. The ubiquity of 
venereal syphilis is striking as compared to the truly focal and limited area 
where pinta is found. Endemic syphilis and yaws are intermediate in this 
respect. These differences are paralleled by the mode of transmission: 
venereal syphilis largely spreads through sexual contact ; the others, largely 
nonvenereal. The above differences apparently are determined to a great 
extent by the social and physical environment in which the host finds 
himself: the more primitive the culture, the less venereal transmission. It 
is believed by many that these environmental variations are the real deter- 
minants of the differences among the strains of treponemes, the manifesta- 
tions in the individual human host and the human population as a whole 
in a given area. Certainly the variation in mode of transmission, the age 
distribution of the disease, the early and, possibly, even the late manifesta- 
tions of the disease in the individual can be logically explained on this basis. 

Before leaving this portion of the discussion, it should be pointed out 
that there have been many observations made during the study of experi- 
mental and naturally occurring syphilis that tend to support this view. 
One, the change in the types of lesions produced by strains following 
passage in rabbits, has already been mentioned. Another bit of evidence of 
great pertinence has to do with the effect of temperature. Both in vitro and 
in vivo experiments indicate that the optimum temperature for the trepo- 
nemes is 35° to 37° C. ; that as 40° C. is approached or exceeded there is 



Table 1. A Summary Presentation of Information Regarding the Etiologic 

Agents^ Clinical Course in Man and Certain Epidemiologic Aspects 

of Syphilis {Venereal), Endemic Syphilis, Taws and Pinta 



syphilis 

(venereal) 



ENDEMIC 
SYPHILIS 



1. The Etiologic Agent 

a. Name T. -pallidum T. pallidum T. pertenue T. carateum 

b. Microscopic Characteristics 

Morphology Indistinguishable for all 

Motility Indistinguishable for all 

c. Antigenic Relationships (in 

animals) 

(1) Serologic tests Apparent strain differences even in same species 

but no constant differences 

(2) Cross-immunity Definite between species but not equal for all: syphilis tends to produce 

greater protection against endemic syphilis than against yaws 

d. Susceptibility to Penicillin. . No significant differences in vitro or in laboratory animals 

e. Experimental Disease in Ani- 

mals 

(1) Establishment of strain. Relatively easy Relatively easy Relatively easy Extremely 

difficult 

(2) Inoculation period (days) 

Number of strains 31 5 11 — 

Minimum-maximum 14-82 53-70 28-75 — 

Median 40 67 52 — 

(3) Lesions (rabbits) , indura- 
tion and size Generally more Generally inter- Generally less — 

mediate 
(Differences not constant or absolute) 

2. Clinical Information 

a. Incubation Period (days) 

Range 10-90 10-90 10-90 7-20 

Median 21 42 (?) 21-42 (?) (human 

inoculations) 

b. Natural Course 

(1) Initial lesions Usual Occur, but com- Usual Occur 

monly not 
noted 

(2) Latency Practically Practically Practically Occurs 

universal universal universal 

(3) Late "benign" Not uncommon Common Usual Usual 

(4) Cardiovascular system. . Not uncommon Occurs Not proved No 

(5) Centra) nervous system. Not uncommon Occurs Not proved No 

c. Serologic Findings with Was- 

sermann or Treponemal An- 
tigens AH positive; no definite or constant differences demonstrated 

d. Response to Antibiotics, Ar- 

senicals and Heavy Metals All respond but time-dose requirements for cure vary 

3. Epidemiologic Information 

a. Distribution Worldwide Endemic, rural, Endemic, rural. Endemic, rural, 

focal, less de- focal, but focal, under- 

veloped areas widespread in developed 

tropical areas, areas, tropical 
primitive America 

setting 

b. Main Reservoir (human 

only) Young adults Children Children Young persons 

(2-10 years) (4-15 years) 10-30 years) 

c. Transmission 
(1) Person to person 



(a) Venereal 


Common 


Uncommon 


Uncommon 


Not described 


(b) Non venereal 


Uncommon 


Common 


Common 


Common 


(c) In iitero . . 


Not uncommon 


Unusual 


Never (some 
contrary 


Not described 












opinion)^ 




(2) Indirect 










(a) Utensils, flies, etc. . . 


Rare 


Probably not 
uncommon 


Possibly not 
uncommon 


Not described 


d. Susceptibility of Man 


Universal 


Universal 


Presumably 
universal 


Presumably 
universal 


e. Period of Communicability 


Variable; during 


Variable; while 


Variable; while 


Unknown; 


in Man 


primary and 


moist skin 


moist lesions 


potentially 




secondary 


and mucous 


present; 


while active 




stages; 


membrane 


(?) several 


skin lesions 




(?) 2-4 years 


lesions present 
(?) weeks to 
months 


years 


present 



723 



724 John C. Hume 

progressive destruction of treponemes; and as the temperature falls below 
30° C, multiplication ceases. These facts certainly have major implications 
regarding the location and nature of lesions in the individual and thus, 
indirectly, for the mode of transmission. Elevated temperature in a host 
as a result of intercurrent infection could affect the transmission of infection 
and the frequency of late manifestations in a population. Other factors 
studied which may have significance include the variation in manifestations 
of disease relative to the age of the host at the time of infection ; the effect 
of the health status of the rabbit host on ease of infection; hormonal 
effects on manifestations of disease; site of inoculation; effect of dosage on 
incubation period and number of lesions; the optimal conditions provided 
by moisture and relative anaerobiosis; and the effect on infectiousness of 
lesions of ''sensitization" of treponemes with the development of immunity 
in the host. Since, however, the purpose of this discussion is to provide a 
basis for considering certain problems in diagnosis and not to support or 
deny the unitarian concept of ''treponematosis," it does not seem profitable 
to pursue this aspect in further detail. 



DIFFERENTIATION FROM NONTREPONEMAL DISEASE 

Let us now consider briefly the differentiation of treponemal from 
nontreponemal disease. Suffice it to say that the vast majority of cases of 
treponemal disease may be readily differentiated from nontreponemal dis- 
ease by the application of simple history-taking techniques, physical exami- 
nation, and serologic tests. Where available, darkfield examination adds a 
great deal to precision of diagnosis. In a small minority of cases, on a 
worldwide basis, the ruling out of other disease processes including biologic 
false positive serologic tests may test the mettle of the most skilled clinician ; 
indeed, it may be impossible. This latter group of cases is certainly of 
extreme importance to the individual patient and physician. The higher 
the level of medical practice and the lower the prevalence of treponemal 
infection in a nation or community, the more importance these problems 
assume. Nevertheless, in terms of global problems of control or eradication 
and of numbers of persons involved, they currently are of far less import 
than certain other difl&culties which will be discussed later. 



DIFFERENTIATION AMONG THE TREPONEMAL DISEASES 

Differentiation of the treponemal diseases, one from the other, has 
already been touched upon. It has been pointed out that the clinical and 
serologic differences are largely quantitative in nature and in the individual 
patient it is difficult or impossible to distinguish one form from the other 
on these grounds alone. For example, we have seen in the Johns Hopkins 



PLATE IV 





A. Patient from Africa with endemic B. Patient from Baltimore, Maryland, 

syphilis. (Courtesy C. J. Hackett, WHO, with syphilis. 
Geneva.) 

A and B depict mucous patches of the lip. Both patients are males; the 
patient in A is a child of approximately 4 years of age; the patient in B is 
approximately 12 years of age. 





C. Patient from Baltimore, Maryland, D. Patient from Haiti with yaws, 

with syphilis. 

C and D depict condylomata lata. The patient in C is a 10 year old girl; 
that in D, a younger child. 

These illustrations show perfectly typical lesions in patients having diagnoses of syph- 
ilis, endemic syphilis or yaws. All are highly infectious, early lesions, teeming with 
treponemes. 



Worldwide Problems in the Diagnosis of Syphilis 725 

Hospital a patient with signs, symptoms and laboratory evidence abso- 
lutely typical of pinta. However, the diagnosis made was that of syphilis 
since she had never been more than 50 miles from Baltimore in her life. 
Similar experiences occur in all large clinics, and venereal syphilis, endemic 
syphilis and yaws even more frequently present confusing similarities of 
expression. In areas where patients are seen who come from both ' 'syphilis 
areas" and ''yaws areas," this may be an interesting problem as recently 
discussed by Laird. ^ In terms of precision of diagnosis and personal clinical 
satisfaction, this is a problem of importance. In terms of successful manage- 
ment of the patient and protection of the public health, however, it has 
little significance under most circumstances. If treatment adequate for the 
cure of syphilis is administered, the patient is cured and the public health 
is protected. The coexistence of venereal syphilis in an urban area and 
yaws in the surrounding rural areas with varying admixtures of each have, 
of course, real significance for the planning of campaigns against the 
treponematoses. (See Plates IV and V.) 



THE MAJOR PROBLEMS IN DIAGNOSIS 

Today the major practical problems in diagnosis are related to such 
questions as: By whom is the diagnosis to be made? What diagnostic 
methods, if any, are to be employed? What constitutes a diagnosis? To 
what groups are these methods to be applied? 

The question of by whom the diagnosis is to be made is a most pressing 
problem in most areas, although there are two aspects. The first is in those 
areas where there is a favorable physician-to-population ratio and a low 
treponemal disease rate. Here arises the paradoxical situation of more and 
more physicians knowing less and less about treponemal disease. As the 
disease rates fall, clinical material becomes less available for teaching, and 
the problem assumes less and less importance, not only in the mind of the 
public in general but among legislators, public health officials, and practi- 
tioners and teachers of medicine. There is no ready and universally appli- 
cable panacea for this. Basically the answer lies in keeping the importance 
of the problem before each of the groups mentioned: teachers must be 
encouraged to maintain an awareness of the presence and importance of 
the treponematoses and to take advantage of each opportunity to demon- 
strate clinical material both intramural and extramural as it becomes 
available. 

The other aspect of the problem is seen in areas where the physician- 
to-population ratio and at times the caliber of physician is low while the 
prevalence of treponemal disease is high. In this situation there are two 
approaches. One, a long-term solution, is the development of more and 
better educational institutions. The other is modification of control or 
eradication programs so that highly trained professional persons are re- 



728 John C. Hume 

mation regarding the effect of inadequate penicillin therapy of rabbit 
syphilis during the incubation period. Hollander, Turner and Nell^ demon- 
strated that the incubation period was prolonged but that otherwise the 
evolution of the disease was apparently unaltered. Similar effects in humans 
would not necessarily be harmful to the patient or the community. If, 
however, continued or repeated subcurative treatment is given, there is 
some question as to whether or not the process may be masked in such a 
way as to allow many cases unsuspectingly to enter latency and subse- 
quently to develop infectious relapse or late manifestations of the disease. 
It seems quite possible that this may indeed be the case. The dispropor- 
tionate fall in reported primary and secondary syphilis as opposed to early 
latent syphilis in young adults noted in certain areas has been interpreted 
as confirmatory evidence. The possibility that subcurative treatment and 
consequent masking of symptoms is the cause of this discrepancy is 
postulated. Up to now the verdict must be ''not proved." In a disease 
where a large portion of the cases have always reached latency without 
recognized symptoms of early disease, such evidence is less than conclusive 
even though suggestive. Certainly we do not know now and possibly 
never will know whether this inadvertent therapy is in balance more 
helpful than harmful in controlling the treponeme. I judge that for the 
community it is probably more helpful. 

Finally, let us consider very briefly certain situations in which, in any 
country, treatment before clinical diagnosis may be justified. In such 
instances one might claim that an epidemiologic diagnosis had been 
established. For many years in most medical centers, it has been consid- 
ered proper to treat immediately individuals who have been exposed to 
infection by such accidents as pricking of the finger with a contaminated 
needle. Even in the arsenical era treatment was administered in certain of 
these accidents by clinicians of undoubted eminence and competence. With 
the advent of the safer and more efficient antibiotics, the frequency with 
which this was done increased, and the criteria for taking such action were 
made less stringent, due attention being paid to the problem of sensitivity. 

Now the matter of how far such prophylactic therapy can be reason- 
ably and beneficially extended has become a subject of importance. Many 
experts will condone such practice in the case of the pregnant woman 
known to be a contact of infectious treponemal disease. Fewer, but still a 
great number, will recommend that all sexual contacts of cases of infectious 
syphilis be given therapy. In my mind there is no question that this latter 
course is justifiable as a community health measure. I believe that the 
hazards of potential psychological disturbances can be largely prevented 
by proper guidance and those of reactions to the antibiotic, by proper 
management. Clinical medicine is based on the weighing of probabilities in 
diagnosis and the possible benefits vs. possible harm in therapy. Each 
clinician and public health worker must make many decisions on this 
basis. So long as this is true and there are not absolute answers to all 



PLATE V 





E. Patient with pinta. (From 

Medichromc series.) 



F. Patient from Africa with 
endemic syphihs. (Courtesy C. J. 
Hackett, WHO, Geneva.) 



Each patient shows typical "late secondary" nodular lesions with nearby 
dyschromic, macular lesions. 





G. Patient with yaws. 
Medichrome series.) 



(From 



H. Patient from Africa with endemic 
syphilis. (Courtesy C. J. Hackett, 
WHO, Geneva.) 



Both patients demonstrate typical destructive late lesions, resulting from 
gummatous osteoperiostitis, which have involved the nasal bones and 
septums. The patient in H also has had involvement of the palate. 

These illustrations demonstrate perfectly typical lesions in patients with pinta, endemic 
syphilis or yaws. In E and F are shown lesions in which treponemes can be demonstrated 
but are relatively noninfectious. In G and H are shown late, destructive manifestations. 



Worldwide Problems in the Diagnosis of Syphilis 729 

diagnostic and therapeutic questions, there will be differences of opinion. 
In this particular instance it would appear to me that what is best for the 
community is also best for the patient. 



SUMMARY AND CONCLUSIONS 

Several problems related to the diagnosis of treponemal disease have 
been raised, some opinions expressed and no quick and easy solutions 
outlined. In the more developed areas of the world, great strides have 
been made since World War II in the control of venereal syphilis. While 
there has been evidence of increasing rates in most of these areas, the 
rates are probably still well below those of the middle 1940's. There is 
some evidence of renewed interest in the problem among the general 
public and public health officials which augurs, it is hoped, a new down- 
ward trend in the incidence of syphilis. In other areas, tremendous efforts 
have been directed toward the elimination of endemic syphilis, yaws and 
pinta. During the period 1950-1962, national mass campaigns have the 
following achievements to their credit: 285 million persons examined in 
surveys and resurveys in 45 countries; 38 million of these persons were 
treated with long-acting penicillin. In the rural areas of these countries, 
the prevalence of active cases dropped from 10-20 per cent to generally 
less than 0.5 per cent. Probably 100 million persons still live in endemic 
areas where 30 to 40 per cent of the population have treponemal infections 
and where little or no systematic control effort has been expended.^ 

While the practicing syphilologist seems to be a species doomed to 
extinction in this country, the treponematoses are still with us and will 
continue to be for some time, though in the long run the treponeme also, 
it is hoped, is doomed. Until this happy state of affairs is reached there 
will continue to be problems facing the health professions in their efforts 
to eliminate the treponeme. The problems will change in nature as progress 
is made toward the goal. Until that goal is attained it is essential that an 
adequate group of interested, well-trained and dedicated workers be 
available to carry on the good fight. 



REFERENCES 

1. Turner, T. B. and Hollander, D. H.: Biology of the Treponematoses. Monograph 

Series No. 35, World Health Organization, Geneva, 1957. 

2. Engelhardt, H. K.: A study of yaws (Does congenital yaws occur?) J. Trop. Med. & 

Hyg. 62: 238-40 (Oct.) 1959. 

3. Laird, S. M.: Yaws in Manchester. Brit. J. Ven. Dis. 31: 30-32 (March) 1955. 

4. Willcox, R. R.: Treatment before diagnosis in venereology. Brit. J. Ven. Dis. 30: 

7-12 (March) 1954. 

5. King, A. J.: For and against treatment before diagnosis. Brit. J. Ven. Dis. 30: 13-16 

(March) 1954. 



730 John C. Hume 

6. Guthe, T.: Treponematoses as a world problem. Brit. J. Ven. Dis. 36: 67-77 (June) 

1960. 

7. Hackett, C. J.: Some epidemiological aspects of yaws eradication. Bull. World Health 

Org. 23: 739-761, 1960. 

8. Hollander, D. H., Turner, T. B. and Nell, E. E.: Effect of long continued subcurative 

doses of penicillin during the incubation period of experimental syphilis. Bull. 
Johns Hopkins Hosp. 90: 105-120 (Feb.) 1952. 

9. Candau, M. G.: The Work of WHO, 1962. Annual Report of the Director-General 

of the World Health Organization and to the United Nations, World Health 
Organization, Geneva, 1963, p. 7. 

The Johns Hopkins University 
School of Hygiene and Public Health 
Baltimore, Maryland 



New Laboratory Methods in the 
Diagnosis and Management of SyphiUs 



EUGENE J. GILLESPIE, M.D.* 
BOBBY C. BROWN, M.D.** 



REAGIN TESTS 

Ever since the first report of the Wassermann reaction in 1906, the 
physician has often been faced with the problem of correctly interpreting 
and coordinating the results of various nontreponemal serological tests for 
syphilis with the clinical findings. Improvement in methods and materials, 
particularly the purification of antigen in the form of cardiolipin, has not 
eliminated the false positive reactions that sometimes occur with comple- 
ment-fixation and flocculation tests. This is not surprising in view of the 
fact that all these tests are based on an empirical reaction between a 
nonspecific antigen, consisting of a lipoidal beef-heart extract, and a so- 
called antibody in syphilitic serum called reagin. It is now well appreciated 
that reagin is produced in response to a rather large number of acute and 
chronic conditions which can in turn produce ''biologic false positive" 
tests for syphilis. With the concept in mind that a serological test merely 
detects the presence of antibody and does not diagnose syphilis, it seems 
a little odd to apply the term "specific" to the reagin tests at all. If they 
give positive reactions to reagin-containing serum due to any cause, they 
would necessarily be specific, though not for syphilis. This is not to under- 
rate the value of the reagin tests as valuable diagnostic tests for syphilis. 
Indeed, in certain situations their value far outweighs that of the more 
glamorous treponemal tests, whose clinical value is limited to very nar- 
rowly defined limits. Research and developments in reagin testing have 



Read at, Syphilis: A Symposium, Vanderbilt University School of Medicine, Nashville, 

Tennessee, May 17-18, 1963. 
From the Venereal Disease Branch, Communicable Disease Center, Bureau of State 

Services, Public Health Service, Department of Health, Education, and Welfare, 

Atlanta, Georgia 
* Deputy Chief 
** Assistant to the Chief 

731 



732 Eugene J. Gillespie, Bobby C. Brown 

kept pace with those of treponemal testing and have enhanced their value 
to the physician. Most notable of these new developments has been in the 
area of rapid testing procedures. 

Rapid Screening Tests 

The first of the reagin tests was developed for the main purpose of 
accomplishing the rapid and economical screening of large numbers of 
persons. Time previously lost in allowing for clotting of blood and inac- 
tivation of serum by heating has been eliminated in the Rapid Plasma 
Reagin Test^ (RPR). The antigen suspension used is derived from basic 
VDRL antigen containing cardiolipin, lecithin and cholesterol. The prin- 
ciple of these tests is that a chemical, specifically choline chloride, is 
introduced into the antigen for the purpose of inactivating or inhibiting 
the substances in unheated plasma or serum which interfere with the 
clumping of antigen and antibody. An additional substance, ethylene 
dinitrilo tetracetic acid (EDTA), is added to prevent deterioration of the 
antigen. 

Extension of the principles of the RPR test resulted in the Plasmacrit 
Test,2 where plasma usually discarded after microhematocrit determination 
is used for serological testing, and the Unheated Serum Reagin Test^ 
(USR), which uses unheated serum for testing. This latter test has been 
suggested as a screening test for public health laboratories by eliminating 
the water bath, and saving time normally allocated to the half-hour heat 
inactivation of serum required in the VDRL test. 

The ultimate in new nontreponemal rapid screening tests has been 
developed which can be completed in from four to eight minutes, and 
requires no test tubes, microscope or centrifuge. The test, the RPR Card 
Test,'' utilizes the Brewer Plasma Collection Card and a modified RPR 
antigen. In the testing, three drops of blood from a finger prick are dropped 
onto a keyhole-shaped depression of a card, which is coated with an anti- 
coagulant, and a lectin, a substance which agglutinates the cellular ele- 
ments. After mixing with a toothpick in the circular area of the depression, 
the red and white cells clump, and the plasma will drain into the collection 
slot after tilting of the card. With a graduated capillary tube, the unheated 
plasma is transferred to a plastic coated card containing a series of teardrop 
depressions. A drop of antigen is added, using a needle and plastic dispenser. 
As stated, this antigen suspension is similar to that used in the other rapid 
reagin tests, except that it contains colloidal charcoal, which makes 
macroscopic reading possible. The antigen suspension and plasma are mixed 
thoroughly, spreading the mixture over the entire teardrop. The card is 
then tilted back and forth. Specimens showing clumping of carbon particles 
are read as reactive. Comparison of this test with standard reagin tests has 
shown excellent correlation, except for slightly increased sensitivity which 
is not an undesirable characteristic in a screening test. 

Despite the definite limitation of the nontreponemal tests in detecting 



New Laboratory Methods in Syphilis Diagnosis and Management 733 

only reagin, their value is almost undisputed in the following situations: 
(1) Because of their economy and relative ease of performance, they are 
invaluable as screening tests. To be remembered are the facts that nega- 
tives are to be expected in very early syphilis or in a certain percentage of 
cases of syphilis of many years' duration, and reactive results are found in 
certain acute and chronic illnesses. In the clinical evaluation, such things 
as age, past medical history including venereal disease history, serologic 
history, and physical findings are very important considerations in the 
correct interpretation of a reactive reagin test. (2) When correlated with 
history and clinical evidence of syphilis, a reactive test is confirmatory. 
(3) When used in conjunction with epidemiological investigations, reactive 
results in contacts, suspects or associates are highly significant. (4) When 
reactive in high or rapidly increasing titer, a reactive test is almost diag- 
nostic of syphilis though occasionally false positive reactions are found in 
high titer. (5) When used to follow babies suspected of congenital syphilis, 
a good quantitative reagin test is an excellent diagnostic tool. (6) Finally, 
the serological response following treatment affords an excellent parameter 
of adequacy of treatment. 



TREPONEMAL TESTS 

The definite limitation of the reagin tests provided the constant 
impetus for the development of a serological test specific for syphilis. 
Naturally, this would be directed toward developing an antigen derived 
from the etiologic agent of the disease. Wassermann himself apparently 
had this in mind when he prepared his original antigen from syphilitic 
fetal liver. Many attempts prior to Nelson's description of the Treponema 
Pallidum Immobilization Test (TPI) in 1949 met with little success. 
Then, in less than 15 years, a host of tests have been developed, some of 
academic and research interest only, and some of proven clinical value. 
These developments are the ones usually brought to mind when one 
mentions new methods in the diagnosis and management of syphilis. 
Indeed, this tends to eclipse the efforts in the area of nontreponemal 
testing and gives one the feeling he is dealing with anachronisms. However, 
the treponemal tests themselves suffer from definite limitations. They do 
no more than inform of the immunological status of the patient and do 
not answer the question of whether or not he has syphilis. To understand 
and properly interpret results of treponemal testing, the concept of a 
multiplicity of antibodies arising during the course of syphilis, and knowl- 
edge of the temporal relationship between them are necessary. Because of 
this, it is improbable that there will ever be a single test technique that 
will detect all of these antibodies. 

Treponemal testing has found its greatest value in one of the following 
three areas: (1) to help distinguish between biologic false positive and true 



734 Eugene J. Gillespie, Bobby C. Brown 

positive reagin tests for syphilis. It is interesting that in any series of 
so-called biologic false positives (BFP's) studied, about 50 per cent will 
ultimately prove to be due to syphilis; (2) to help establish a correct 
diagnosis in patients who have clinical evidence of syphilis, particularly 
late syphilis, but who have nonreactive blood and spinal fluid reagin tests, 
and (3) to assist in the diagnosis in patients who epidemiologically should 
have the disease, but who have negative clinical serological evidence. The 
latter refers to a diagnosis of syphilis in a marital partner, or a mother 
who is seronegative with a congenitally syphilitic child. With these indi- 
cations for treponemal testing in mind, the next questions would be: (1) to 
what extent reactive results may be considered evidence of past or present 
syphilis, and (2) to what extent may nonreactive results be considered 
indicators for the absence of past or present syphilis? In other words, what 
is the specificity and sensitivity of the various treponemal tests? In the 
discussion to follow, a chronological presentation of the treponemal tests 
will be given. Points to be covered are a brief presentation of the test 
procedures, advantages and disadvantages of the test proper, and usefulness 
as a clinical and research test. 

Treponema Pallidum Immobilization Test 

The era of treponemal testing began in 1949 when Nelson and Mayer 
described the immobilization of treponemes by syphilitic serum in the 
presence of complement.^ In the test itself, virulent Treponema 'pallidum 
are extracted from rabbit testicles and placed in survival media. The serum 
to be tested and complement are added and this is then allowed to incubate 
for a period of time. Following this, the percentage of treponemes immo- 
bilized as compared to controls are counted, with the result based on this 
count. In theory, the test is simple) in practice, it is difficult. Laboratories 
performing this test must maintain a rabbit colony for a ready source of 
living treponemes. Highly trained and skilled technicians are necessary to 
assure reproducibility of the test. It is important to emphasize that the 
TPI is no single test. Procedures vary from one laboratory to another. 
Some pretreat the rabbits with corticosteroids or x-ray as a means of 
reducing supposedly sensitized treponemes. Others do not. Differences are 
encountered in the amount of thioglycolate added to the survival media, 
amount of complement added, length of incubation time, and number of 
treponemes counted. Thus, results can vary on the basis of procedure 
performed. It is surprising how many supposedly TPI nonreactive bloods 
from one laboratory will be reactive in another. Some knowledge of the 
actual procedures should be available to persons interpreting results. 
Because of the difficulty of the technical procedure and the great cost 
involved, very few laboratories have adopted this test. Also, the variability 
inherent in a test, that must employ an antigen of unknown and variable 
sensitivity for each day's run, gives the serologist considerable uneasiness. 
Clinically, however, the TPI test, despite these technical problems, has 



New Laboratory Methods in Syphilis Diagnosis and Management 735 

proved a tool of the first magnitude permitting the resolution of many 
diagnostic problems that have heretofore defied other serological tech- 
niques.^- 7, 8, 9. 10 With the knowledge that the TPI may be nonreactive in 
two-thirds of patients with primary syphilis and one-third of patients with 
secondary syphilis, it can be stated that the TPI will be reactive in essen- 
tially all other stages of syphilis and, of course, other treponematoses.^^- ^2. 13 
Thus, it is readily applicable to the diagnostic categories initially outlined. 
Because of its great specificity, all subsequent treponemal tests have been 
compared to this test and it has subsequently become a sort of standard. 
From a practical standpoint, however, there still remained a need for a 
specific serological test, which could be performed in the average serological 
laboratory, would be highly reproducible, and could be performed with a 
minimum of materials. 

Treponema Pallidum Agglutination Test 

The first effort in this pursuit was in the study of agglutination of 
spirochetes by syphilitic sera. Prior to the years 1953-55, efforts in this 
area had always ended in failure because it had been found that Treponema 
pallidum spontaneously agglutinated. McLeod,^^ extending the work of 
Japanese investigators who found that treatment of Treponema pallidum 
with weak hypochlorite solution would destroy the tendency of spontaneous 
agglutination, showed that heating produced the same results. Subse- 
quently, she developed a test, Treponema Pallidum Agglutination (TPA), 
based on this principle, which showed fair correlation with the TPI on 
initial selected sera. In the actual test, heat-killed treponemes were 
agglutinated by syphilitic sera in the presence of fresh bovine sera contain- 
ing both complement and conglutin. On further evaluation, however, it 
was found that serum containing reagin unrelated to syphilis could agglu- 
tinate Treponema pallidum and hence the test lost its potential clinical 
value. ^^ 

Treponema Pallidum Immune Adherence Test 

During this same period. Nelson^ ^ described the phenomenon of 
adherence of treponemes to erythrocytes, sensitized with syphilitic serum, 
in the presence of complement. Following gentle centrifugation, the red 
cells would drop to the bottom of the tube, taking treponemes with them 
in a reactive result. In a nonreactive result, darkfield examination of the 
supernate is positive for Treponema pallidum. Comparison of the test 
derived from this phenomenon, Treponema Pallidum Immune Adherence 
(TPIA), with the TPI has shown it to be roughly equivalent.^^- ^^ There 
developed some problems in reading of the test concerning what con- 
stituted a negative, weakly reactive and reactive, but subsequent work 
helped solve some of this. In actual practice, this procedure suffered from 
at least one serious defect— that of requiring living virulent treponemes. 
However, in 1957, Miller^^ described the preparation of heat-killed organ- 



736 Eugene J. Gillespie, Bobby C. Brown 

isms suspended in saline, and preserved by thiomerosal (Merthiolate) 
solution, which potentially could extend widely the usefulness of this test. 
The literature contains no recent experience on this subject. 

Treponema Pallidum Complement Fixation Test 

The appearance of the Treponema Pallidum Complement Fixation 
Test (TPCF)2o introduced a new concept in treponemal testing. This 
represented the first time that an antigenic moity was extracted from 
treponemes ''defatted" by acetone and ether with a solution of desoxy- 
cholate. Immediately, certain difficulties became evident in that the source 
of this material (virulent living Treponema 'pallidum) was in short supply. 
More of a problem, however, was the rather large number of normal sera 
giving positive reactions to the test. The first problem was ameliorated to 
a degree, by the introduction of testing using small volumes of reagents,^^ 
but the second persisted with up to 13 per cent of nonsyphilitic sera giving 
false positive results. ^^ Because of the attractive feature of this technique 
being so readily adaptable to the average serological laboratory, the 
antigen did become commercially available. More recent work by McLeod,^^ 
however, has indicated another potential difficulty with the TPCF antigen. 
She found that the injection of this material not only formed a TPCF 
antibody, but reagin as well. It could be postulated that this impure 
antigen could produce false positive reactions in reagin-containing serum — 
one of the clinical areas where a conffi-matory test is most needed. 

Treponema Pallidum Methylene Blue Test 

In 1956, an interesting modification of the TPI was described. This 
test, called the Treponema Pallidum Methylene Blue Test (TPMB),24 
is based on the inhibition of staining of Treponema pallidum, once it has 
become sensitized or perhaps coated with antibody. The test is performed 
in the same manner as the TPI, except methylene blue is added at the 
end of the incubation period with readings dependent on staining or lack 
of staining of treponemes by the dye. The test has all of the advantages 
and disadvantages of the TPI and most believe it adds little to the original 
test, especially if one is dealing with motile treponemes. It is thought, 
though, that the test certainly merits more evaluation and testing with the 
exciting possibility in mind that perhaps dead or desiccated Treponema 
pallidum could be used in the test. With this, the simple presence or 
absence of red color (methylene blue stained organisms are red under 
darkfield light) in the organism could determine presence or absence of 
antibody, with lack of staining indicating a reactive result. 

Whole-Body Treponema Pallidum Complement Fixation Test 

Cohen, in 1956, introduced a complement fixation test, the Whole- 
Body Treponema Pallidum Complement Fixation Test (WTPCF),^^ using 
phenol-treated Treponema pallidum as an antigen in a one-fifth volume 



New Laboratory Methods in Syphilis Diagnosis and Management 737 

Kolmer complement fixation test. The preliminary results reported in the 
paper are roughly in agreement with the TPI on a limited number of sera; 
however, no wide evaluation of the technique is available. 

The year 1957 saw the introduction of a number of new procedures. 
Two of these, the Reiter Complement Fixation Test (RCFT) and the 
Treponemal Wassermann Reaction Test (TWR) have had little develop- 
ment and evaluation, while the other two, the Reiter Protein Complement 
Fixation Test (RPCF) and the Fluorescent Treponemal Antibody Test 
(FTA) have had extensive evaluation and application. 

Reiter Complement Fixation Test 

The Reiter Complement Fixation Test (RCFT)^^ employs as antigen 
a suspension of Reiter organisms in a phenol-saline solution. Testing 
technique is the one-fifth volume Kolmer. While the preliminary report 
showed that the test was more specific than the reagin tests in problem 
sera, and also more sensitive in late symptomatic and untreated early 
syphilis, its overall performance was far below that of the TPI. No further 
evaluations are available. 

Treponemal Wassermann Reaction 

The Treponemal Wassermann Reaction Test (TWR)"- ^^ enjoyed 
a brief period of popularity in the English literature as a test which com- 
pared favorably with the TPI in sensitivity and specificity, but which 
became reactive sooner than the TPI in early syphilis but also became 
nonreactive sooner than the TPI following successful treatment. The test 
utilized antigen derived from Treponema pallidum ''cut up" with ground 
glass on a shaking machine in a complement fixation reaction. On further 
evaluation, however, the test was found to produce a large number of false 
positive results, and furthermore, the results were not reproducible.^^ 

Reiter Protein Complement Fixation Test 

Work by D'Allesandro and Dardanoni^° on protein extracts from the 
nonpathogenic Reiter organism showed this material to be antigenic and 
capable of reacting with syphilitic sera. The protein antigen used in the 
Reiter Protein Complement Fixation Test (RPCF) is extracted by sub- 
jecting the organism to 75 freeze-thaw cycles in dry ice-acetone with 
subsequent precipitation of the protein using concentrated ammonium 
sulfate solution. The material so obtained is employed in a one-fifth volume 
Kolmer complement fixation test^^ (RPCF). To recommend its use, an 
inexpensive and readily available antigen is used and the basic testing 
procedure is performed in most laboratories. When this test was evaluated 
in the Public Health Service sponsored study designated as SERA or 
Serology Evaluation and Research Assembly, its sensitivity and specificity 
appeared to be quite satisfactory, being similar generally to the TPI test. 
Subsequently, because of the initial favorable evaluations, the test was 



738 Eugene J. Gillespie, Bobby C. Brown 

widely adopted by State public health laboratories to be performed as a 
sequel to the positive nontreponemal tests from patients not previously 
diagnosed as having syphilis. After several years of actual application, its 
value and limitations can be more adequately assessed. Unfortunately, the 
original enthusiasm, that the procedure might serve as a satisfactory 
substitute for the more complex and expensive TPI test, has been shown 
by more recent evaluation to be premature. The Reiter test has had a low 
correlation with the TPI test in the group of patients in which serologic 
confirmation is most needed; that is, in cases characterized by no clinical 
or historical evidence of syphilis and a reactive reagin test. This lack of 
good agreement apparently is the result of a lesser sensitivity of the Reiter 
test. In a study of syphilis of long standing in the male Negro, the RPCF 
was much less reactive than the TPI test; the difference was even greater 
in those patients having inadequate treatment than in those having had 
no treatment. On the basis of these and other studies, it was indicated that 
in interpreting results in syphilis of long duration, whether treated or 
untreated, the chances are that Reiter tests will be nonreactive more than 
50 per cent of the time. ^2, 33 Although most of the concern has been the 
lack of sensitivity, at least one recent report has pointed to the occurrence 
of biologic false positive reactions with the test.^"* Efforts to correct some 
of the shortcomings of the test have met with some success; for example, 
it has been found that the sensitivity can be increased following freezing 
and reheating of serums,^^ but in the light of very recent investigations, 
which show that the Reiter treponemes share common antigens not only 
with Treponema 'pallidum but also with mouth and saprophytic trepo- 
nemes,^^ it is doubtful that the RPCF will ever achieve the initial high 
hopes for the test. 

Fluorescent Treponemal Antibody Test 

The Fluorescent Treponemal Antibody Test (FTA)" is, in principle, 
an application of the indirect fluorescent antibody procedure. Antigen 
consisting of a suspension of the Nichol's strain of Treponema pallidum is 
dried on a slide and overlaid with the unknown serum. Should it contain 
antibody, it will react with the organism, depositing an invisible layer of 
antibodies. This is then treated with a fluorescein-tagged antibody to 
human globulin. If globulin (syphilitic antibody) coated the treponeme, 
the tagged material reacts with it and the treponeme will fluoresce when 
viewed under ultraviolet light. If no globulin coated the treponeme, no 
tagged antibody reaction will occur and no fluorescence is observed. When 
first published, a 1 : 5 dilution of serum was employed, but with the dis- 
covery of a more efficient fluorescent conjugate, fluorescein isothiocyanate, 
it became necessary because of a large number of nonspecific reactions 
produced, to modify the test so that a 1 : 200 dilution of serum is used. 
This revised technique, the FTA-200,^^ was found to have a greater repro- 
ducibilitj^ than the original test. In addition, the high specificity has been 



New Laboratory Methods in Syphilis Diagnosis and Management 739 

retained, but because of the dilutional factor, the sensitivity has been 
reduced. Studies^^ recently completed and currently in progress to increase 
the sensitivity without loss of specificity of the test are of considerable 
interest. These studies show that at least one antigen (Reiter protein 
antigen) is found to be a common or shared component of the four trepo- 
nemes studied: Treponema pallidum, the Reiter treponeme, Treponema 
zuelzerae, a free growing mud treponeme, and Treponema microdentium. 
Through absorption studies, however, a specific antigen of each organism 
could be identified. It is possible that nonsyphilitic treponemal antibodies 
detected by the FT A test when a 1 : 5 dilution is used are due to the anti- 
bodies directed against the mouth treponemes. By absorption of the 
antibodies directed against these common antigens, it should be possible 
to greatly increase the sensitivity of the If'TA test, making unnecessary 
the 1 : 200 dilution, as well as slightly increasing its specificity. Another 
problem with the FTA has been that of background fluorescence of debris. 
This problem seems near solution, however, with the suggestion that this 
debris may be counterstained with Evans Blue which fluoresces red under 
ultraviolet light, thus affording a good contrast to the specific green 
fluorescence.^^ 

The advantages of this test are evident. Desiccated treponemes can 
be supplied to laboratories from a central supply laboratory, as well as the 
conjugated antihuman globulin. The greatest technical disadvantage at 
the moment is that of the cost of ultraviolet equipment, but with the 
continued growth of the fluorescent antibody technique as a research and 
diagnostic tool in other areas, purchase by laboratories is justified. 

Initial evaluation of the FTA test has been very favorable even with 
the 1 : 200 serum dilution requirement. The development of antibody as 
shown by the technique closely parallels the presence of immobilizing 
antibody except that it appears much earlier in most cases. ^° The FTA 
gives highest titers in secondary syphilis and following treatment will show 
a reduction in titer, but over a much longer period than the VDRL, for 
example. 

Other Tests 

Despite the rather momentous significance of the tests just discussed, 
work continued on development of additional techniques. This work 
resulted in the Treponema Pallidum Cryolysis Protein Test (TPCP)''^ 
which is identical to the RPCF except that it uses the virulent Treponema 
pallidum as an antigen source and more recently (1961) the Reiter 
Fluorescent Treponemal Antibody Test (RFTA)'^^ j^^s appeared. Even 
though this and a later modification using hypochlorite washed organisms 
show some favorable reports,^^ the prediction would be, on the basis of the 
common antigen shared by Reiter, with other treponemes, that this test 
would ultimately prove to be nonspecific. 

From this confusion of ''alphabet soup" designations, it is hoped that 



740 Eugene J. Gillespie, Bobby C. Brown 

one test procedure will ultimately be devised that can best answer the 
needs of the clinician, as initially set forth in this paper. Despite certain 
limitations, however, the tools are available now for the proper diagnosis 
and management of the overwhelming majority of patients. 



REFERENCES 

1. Portnoy, J., Garson, W. and Smith, C. A.: Rapid Plasma Reagin Test for syphilis. 

Pub. Health Rep. 72: 761-766, 1957. 

2. Andujar, J. J. and Mazurek, E. E. : The Plasmacrit Test on capillary blood. Am. J. 

Clin. Path. 31: 197-204, 1959. 

3. Portnoy, J., Bossak, H. N., Falcone, V. and Harris, A.: Rapid Plasma Reagin Test 

with unheated serum and new improved antigen suspension. Pub. Health Rep. 76: 
933-935, 1961. 

4. Portnoy, J., Brewer, J. H. and Harris, A.: Rapid Plasma Reagin Card Test for 

syphilis and other treponematoses. Pub. Health Rep. 77: 645-652, 1962. 

5. Nelson, R. A., Jr. and Mayer, M. M.: Immobilization of Treponema pallidum'm vitro 

by antibody produced in syphilitic infection. J. Exper. Med. 89: 369-393, 1949. 

6. Durel, P., Sausse, A. and Borel, L. J.: Treponemal Immobilization Test. Brit. J. 

Ven. Dis. 28: 68-79, 1952. 

7. Miller, J. L., Slatkin, M. H., Feiner, R. R., Portnoy, J. and Cannon, A. B.: Trepo- 

nemal Immobilization Test. J.A.M.A. 149: 987-991, 1952. 

8. Miller, J. L., Slatkin, M. H., Lupton, E. S. and Brodey, M.: Studies on the value 

of the Treponema Pallidum Immobilization Test in the diagnosis of syphilis. 
Am. J. Syph. 36: 559-565, 1952. 

9. Chacko, C. W. : Clinical value of the Treponema Immobilization Test in the diagnosis 

and control of syphilis. J. Clin. Path. 6: 227-231, 1953. 

10. Nielsen, H. A.: Clinical value of the Treponema Pallidum Immobilization Test. 

Acta dermat.-venereol. 34: 102-109, 1954. 

11. Edmundson, W. F., Ackerman, J. H., Guiteirrez-Salinas, E. and Olansky, S.: Study 

of Treponema PaUidum Immobilization Test in clinical syphilis. A.M. A. Arch. 
Dermat. & Syph. 70: 298-301, 1954. 

12. Edmundson, W. F., Kamp, M. and Olansky, S.: Study of the Treponema Pallidum 

Immobilization Test in clinical syphilis. A.M. A. Arch. Dermat. 71: 384-386, 
1955. 

13. Edmundson, W. F., Olansky, S., Wood, C. E. and Kamp, M.: Study of Treponema 

Pallidum Immobilization Test in clinical syphilis. A.M. A. Arch. Dermat. 71: 387, 
1955. 

14. McLeod, C. P. and Magnuson, H. J.: Agglutination of T. pallidum in syphilitic 

serums. Pub. Health Rep. ^5; 747-755, 1953. 

15. McLeod, C. P. and Stokes, P. S.: Agglutination of Treponema pallidum by reagin 

antibody. Pub. Health Rep. 70: 379-383, 1955. 

16. Nelson, R. A., Jr.: The immune-adherence phenomenon. Science 118: 733-737, 1953. 

17. Olansky, S., Harris, A. and Casey, H.: Immune- Adherence Test for syphilis. Pub. 

Health Rep. 67: 521-526, 1954. 

18. Miller, J. N., Boak, R. A. and Carpenter, C. M.: Treponema Pallidum Immune- 

Adherence Test in the diagnosis of syphihs. J.A.M.A. 163: 112-114, 1959. 

19. Miller, J. N., Boak, R. A. and Carpenter, C. M.: A stable antigen for the Treponema 

Pallidum Immune Adherence Test for syphilis. Am. J. Clin. Path. 32: 187-191, 
1959. 

20. Portnoy, J. and Magnuson, H. J.: Treponema Pallidum Complement-Fixation Test 

for syphilis. Am. J. Clin. Path. 26: 313-322, 1956. 

21. Portnoy, Joseph: Complement-fixation with small volume of reagents. Am. J. Clin. 

Path. 31: 316-322, 1959. 

22. Bossak, H. N., Duncan, W. P., Harris, A. and Falcone, V.: Evaluation of TPCF 50 



New Laboratory Methods in Syphilis Diagnosis and Management 741 

Test and other Treponema pallidum complement fixation tests for syphilis diagnosis 
Pub. Health Rep. 75: 130-134, 1960. 

23. McLeod, C. P.: Relationship between Treponema pallidum complement fixation 

antigen and reagin. Pub. Health Rep. 77: 441-445, 1962. 

24. Rosenau, B. J. and Kent, J. F.: Resistance of specifically-sensitized Treponema 

pallidum to methylene blue stain. Proc. Soc. Exper. Biol. & Med. 91: 579-582, 1956. 

25. Cohen, H. A.: Use of whole Treponema pallidum (Nichol strain) in a complement- 

fixation test for the diagnosis of syphilis. J. Invest. Dermat. 27: 364-376, 1956. 

26. Wilkinson, A. E.: Comparison of results given by a complement fixation test using 

the Reiter treponeme as antigen with the Treponemal Immobilization Test. 
Brit. J. Ven. Dis. 33: 25-29, 1957. 

27. Price, I. N. O. and Whelan, M. J.: Preliminary report on a complement fixation 

test for treponematosis (TWR). Brit. J. Ven. Dis. 33: 18-21, 1957. 

28. Price, I. N. O.: Preliminary evaluation of the treponemal Wassermann reaction. 

Brit. J. Ven. Dis. 34: 91-93, 1958. 

29. Dunlap, E. M. C. and Price, I. N. 0.: Clinical assessment o Ithe treponemal Wasser- 

mann reaction. Brit. J. Ven. Dis. 35: 149-161, 1957. 

30. D'AUesandro, G. and Dardanoni, L.: Isolation and purification of the protein 

antigen of the Reiter treponeme. Am. J. Syph. 37: 137-150, 1953. 

31. Cannefax, G. R. and Garson, W.: Reiter Protein Complement-Fixation Test for 

syphilis. Pub. Health Rep. 72: 335-339, 1957. 

32. Brown, W. J. and Bunch, W. L., Jr.: How good is the Reiter Protein Complement- 

Fixation Test for syphilis? South. M. J. 52: 783-787, 1959. 

33. Brown, W. J., Price, E. V. and Simpson, W. G.: The Reiter Protein Antigen Test 

compared with the Treponema Pallidum Immobilization and other treponemal 
and non-treponemal antigen techniques in the diagnosis of syphilis. J. Invest. 
D(^rmat. 34: 223-227, 1960. 

34. Berneu, J. J., King, J. W. and Reich, A.: Evaluation of the Reiter Protein Comple- 

ment Fixation Test for syphilis. Cleveland Clin. Quart. 27: 162, 1960. 

35. Bossak, H. N., Falcone, V. H., Portnoy, J. and Harris, A.: Studies to improve the 

efficacy of the Kolmer test with Reiter protein antigen. Pub. Health Lab. 20: 
105-111, 1962. 

36. Deacon, W. E. and Hunter, E. F.: Antigenic differentiation of treponemes and 

implications in terms of syphilis serology. In press. 

37. Deacon, W. E., Falcone, V. H. and Harris, A.: A fluorescent test for treponemal 

antibodies. Proc. Soc. Exper. Biol. & Med. 96: 477, 1957. 

38. Deacon, W. E., Freeman, E. M. and Harris, A.: Fluorescent Treponemal Antibody 

Test modification based on quantitation (FTA-200) Proc. Soc. Exper. Biol. & 
Med. i 03.- 827-829, 1961. 

39. Fry, C. S. and Wilkinson, A. E.: A note on the use of Evans Blue as a background 

stain in the FTA Test. World Health Org. Bull. WHO/VDT/316; WHO/VDT/ 
RES/35, March, 1963. 

40. Wilkinson, A. E.: FTA Test: A preliminary report. Brit. J. Ven. Dis. 37: 59-63, 1961. 

41. Cannefax, G. R. and Garson, W.: Demonstration of a common antigen in Reiter's 

treponeme and virulent Treponema pallidum. J. Immunol. 82: 198-200, 1959. 

42. Covert, S. V., Kent, J. F. and Stevens, R. W.: Fluorescent Treponemal Antibody 

Test using the Reiter treponeme. Proc. Soc. Exper. Biol. & Med. 106: 729, 1961. 

43. Kent, J. F., Covert, S. V., Reilly, H. W., Kinch, W. H. and Lawson, W. B.: Evalu- 

ation of Fluorescent Treponemal Antibody and other tests for syphilis. Proc. Soc. 
Exper. Biol. & Med. 109: 584-589, 1962. 

Communicable Disease Center 
U. S. Public Health Service 
Atlanta 22, Georgia 



A Glance in Both Directions — 

The Impact of SyphiHs on the Family 



ANNE SWEENEY, M.A. 



About 25 years ago when syphilis control was being vigorously 
promoted by the U.S. Public Health Service and the resulting long lines of 
patients registering for ''arm shots" or ''hip shots" were commonplace 
scenes in the outpatient departments of hospitals and departments of 
public health, a patient* who had faithfully carried out the whole painful 
plan of treatment stopped by to tell me she would be moving to a distant 
state. I have always remembered the terse profundity of her message. She 
said, "Thank you for everything and I hope I never see you again." 

The patient, an intelligent woman in her early twenties, had been 
referred from the Obstetrical Clinic to the Syphilis Clinic because of a 
secondary recurrence. She had earlier received inadequate treatment from 
her private physician, having seemingly never had a clear understanding of 
the disease and the potential consequences. At referral she was four months 
pregnant. 

With some hesitancy the patient revealed her history. A former 
unhappy marriage had ended in desertion at the end of three months. Two 
years afterward she married again and in the present marriage the couple 
had been happy. Shortly after the marriage, however, both she and her 
husband learned they had syphilis, but the disease had apparently been 
accepted as a result of the patient's previous misfortune. Therefore she 
was able to keep her anxiety in check until pregnancy occurred. Then she 
became terrified for fear her child would have syphilis and as a result might 
be deformed. The possibility of having a syphilitic child aggravated her 
guilt about her husband's infection. He, on the other hand, found it hard 
to understand the patient's fears since he was especially happy about the 
advent of a child. His consideration of her seemingly did nothing but 
increase her anxiety. 

Reaching out to this patient with understanding and empathy calmed 
her momentarily and aroused her interest in asking questions in areas 



From the Medical Social Service Department, Vanderbilt University Hospital, Nash- 
ville, Tennessee 



* The case illustrations are true accounts, sufficiently disguised to prevent 
identification. 

743 



744 Anne Sweeney 

which had been so anxiety provoking. It was a relief to her to learn from 
an authoritative agency, the hospital, that her chances of having a healthy 
baby were excellent and that, even should the child have syphilis, it could 
probably be ''cured." 

Throughout the rest of the pregnancy the patient's mental outlook 
improved markedly. She was able to pass on to her husband the education 
which she received. He, too, resumed antisyphilitic treatment. At the time 
of delivery, as was expected, the patient's anxiety increased, but by then 
she had developed confidence in her doctors and could also use well the 
supportive assistance of the social worker. Fortunately the child was a 
full-term, bouncing boy. From the day the patient stopped in to say 
good-by, I have not seen her. But we may hope with some confidence that 
the ghost of syphilis was laid in that family. 

Another patient, a man in his forties, learned of his positive blood 
when he volunteered as a blood donor. He, too, had had antisyphilitic 
treatment many years earlier but not so long before his marriage that he 
could be advised to forget about the need for his wife to be examined as a 
contact. Should her blood be positive, there were five children who would 
also need examination. At first the patient was almost unable to face the 
threat to his whole way of life, but he did measure up to it. The couple, 
for the wife was found to be infected, began antisyphilitic treatment, and 
supported each other through the seemingly endless weeks while the chil- 
dren's status was being cleared. They had partial good fortune in that the 
children had negative examinations. Feeling the concern of the clinic staff 
for them during their ordeal, these patients also shared with them their 
happiness upon finding that the children had been spared. 

The successful campaign against syphilis of the 1930's and 1940's 
eventually did away with the customary swarming Saturday morning 
clinics for school children. As we look back upon the heartbreak which it 
causes, it is certainly to be hoped that the opportunity for congenital 
syphilis to develop will never occur again. One poignant example could be 
multiplied many times over. 

A very bright high school graduate moved from her small town to the 
city to go to work. In the course of a routine examination she was found 
to have a positive blood and, in exploring her history, it was learned that 
as a young child she had had "shots" for a diagnosis unknown to her. A 
younger sister apparently had juvenile paresis but the etiology of the 
psychosis was unknown to the patient. Later her mother wrote : 

"I appreciated the nice letter you wrote concerning Mary's treat- 
ments. The reason I have kept this a secret from her, I thought she might 
be cured without having to know how handicapped she was. It's been such 
a great burden to me, that I didn't want her to suffer what I had suffered. 

"It's her father's fault and ignorance on my part that this happened. It 
is strange at my age I was so ignorant of these things but my mother failed 
to teach me and I happened not to learn otherwise, and so it's almost 
wrecked my home and life. 

"I hope you people will do your best for her. She has tried so hard to 



The Impact of Syphilis on the Family 745 

accomplish something worthwhile. I hope she can set aside the thought of 
her condition and not feel so handicapped. How long do you think she will 
have to continue the treatments? My husband and I took a blood test about 
four years ago. It proved negative. I have been extremely careful since I 
learned about the disease. 

"Each of us has taken the blood test except the youngest daughter. 
She is 15 years of age and seems to have perfect health. Do you think it nec- 
essary for her to have a blood test? I'll be so thankful for any advice you 
may be able to give us." 

This letter from a mother who had never met any of the clinic staff 
but was merely responding to a note expressing interest in her child whose 
ability held a considerable degree of future promise, needs no comment. It 
reveals the lack of information, the misinformation and the years of 
tragedy constantly hovering over the family. Notable in the tragedy is the 
fact that so much of it might have been prevented, since it is not neces- 
sarily the disease itself which does much of the harm, but rather the 
consequent impairment of family relationships. A woman who could so 
simply, so concisely, and yet so feelingly recount her misery from her own 
viewpoint, could probably have solved or at least diluted her emotional 
stress had she been able to share this with an informed, sympathetic person 
who would take time to listen. "Taking time" is a carefully chosen state- 
ment; it is extremely easy in a busy workday not to have time to take on 
oneself the emotional turmoil of others. To do so is sometimes itself 
anxiety-producing; it is demanding also, but will the job of syphilis control 
be accomplished unless dealing with the emotional component is fully 
accepted as a part of the challenge? 

One of the more articulate patients once informed me of the effect 
that he felt from the nonjudgmental attitude of the social worker. Because 
of his feeling of disgrace and the consequent severe emotional reaction, he 
could not discuss with anyone the fears and anxieties which he had been 
secretly storing away in his mind for several months. Until he realized that 
the social worker was not judging him, he reacted defensively. He would 
slink into the hospital, thinking that everyone who saw him enter said, 
"There goes John. He has syphilis." He later remarked that the social 
worker's acceptance of him had helped him immensely to face the situation 
with some objectivity and to try to plan a constructive future. In a sense, 
the social worker represented public opinion. 

In analyzing the difficult situations which patients with syphilis in 
earlier days had to meet we could group them into three broad classifica- 
tions: 

(1) Those within the personality of the patient himself. 

(2) Those which concerned the patient's relationship with his family, 
including the marital problems, fear of having other members of 
the family learn the diagnosis, the wish to avoid causing discord 
at home because of unusual precautions against spreading infec- 
tion, and the problems concerned with the examination of house- 
hold contacts. 



746 Anne Sweeney 

(3) Those which concerned the patient and the community, including 
the patient's work and school arrangements to permit clinic 
attendance, his plans for remaining away from work during the 
infectious stage, and the necessity for examination of contacts 
outside the home. 
What differences do we perceive today? With the development of 
short and less arduous treatment methods, greater ease of obtaining treat- 
ment, most often by arranging a convenient appointment with a private 
physician, many of the practical difficulties have solved themselves. Work 
and school schedules are seldom upset, infectiousness is rapidly controlled, 
easy transportation is generally available, and despite the great increase in 
the cost of living, more people can afford the expense of present-day ther- 
apy. Still to be met, however, are the problems caused by the diagnosis of 
syphilis as it affects the patient's personality, his relationships with his 
family, some of whom may also need to be considered as household con- 
tacts, and the problem of examination of extramarital contacts. Despite 
the fact that today sex is dinner table conversation and our literature and 
films would give the impression that there is little inhibition left, the 
patient who is informed he has syphilis does not as a rule take it casually. 
We might well recognize in the case illustrations from an earlier time some 
of the reactions of today's patients. 

The more sophisticated patient would perhaps now be unlikely to put 
much credence in any talk of easy ' 'innocent" infection. All to the good. 
The doctor, nurse, investigator or social worker ought likewise now be able 
to face the truth more comfortably with the patient and thereby more 
quickly set the stage for a relationship of confidence. For, with the concrete 
difficulties being, in the main, solved, the therapeutic importance of the 
relationship of the patient with the medical and paramedical personnel 
becomes highlighted. Most of the patients will not seek psychiatric care; 
we know such attention could not be made available to the majority of 
patients. The patient will, though, seek the solution of his distress in the 
treatment clinic or in the doctor's office. Moreover, for the contact inves- 
tigator the relationship with the patient is of more than humanitarian 
interest. It is, in fact, the only tool whereby he can obtain information. 
The law cannot force the patient to give data about contacts, but experi- 
ence has shown that the respected patient will usually rise to the request 
made of him. 

A final word. The enthusiasm of the campaign to ''stamp out syphilis" 
was perhaps as infectious as the disease itself. It was a challenge to find 
contacts with only the briefest of descriptions and the address of the 
"hangout." It was even more satisfying to have them request examinations. 
Many of them turned into truly grateful patients. With the patient load 
being more scattered it is harder now to recapture the same enthusiasm, 
but I am convinced that this is an essential ingredient. 

Vanderbilt University Hospital 
Nashville, Tennessee 



Penicillin Fallout and Infectious Syphilis 



WILLIAM F. DANEHOWER, M.D.* 



In May, 1962, the Pennsylvania Medical Journal published a 
short article entitled ^Tenicillin Fallout— Menace or Manna?"^ It called 
attention to two phenomena which no doubt have been observed by many 
physicians : 

1. Penicillin administered to treat one clinically manifest ailment often 
cures simultaneously a second coexisting disease. 

2. During the years (1948-1953) when millions of people were receiving 
penicillin administered (often on slight indication) for a multitude of 
ailments, certain major diseases formerly common virtually vanished from 
the scene. Included in this group were lobar pneumonia, hematogenous 
osteomyelitis, meningococcic and certain streptococcic infections, suppura- 
tive parotitis and syphilis. 

Piecing together these two observations, it was suggested that perhaps 
the near disappearance of these serious diseases was not due primarily to 
penicillin treatment of clinically manifest cases of these diseases. Rather, 
penicillin reached unrecognized early cases and asymptomatic carriers who 
chanced to be ill at the time with an intercurrent ailment for which the 
penicillin was administered. Such ''happenstance" treatment not only 
aborted the disease in the individual; what was more important from the 
public health standpoint, it abbreviated or eliminated his period of infec- 
tiousness to others. As a result, spread of the disease was curbed and the 
incidence of new cases declined. 

Taking infectious syphilis as an example, it was noted that, during 
the years when penicillin was most widely employed for myriad ills, the 
syphihs attack rate declined by 93 per cent. Subsequently, as physicians 
became ever more selective in their use of the drug, the annual number of 
reported early cases promptly tripled. 

These ''off-beat" comments evoked a number of responses, some of 
approval, some of dissent. One of the most interesting, and certainly the 
best formulated, is entitled "An Answer to Penicillin Fallout . . . Menace 
or Manna?" by Popper.^ Briefly his thesis is: 

1. "Happenstance" treatment of early syphilis is inadequate treat- 
ment. 



Physician, Department of General Practice, Germantown Hospital, Philadelphia, Pa. 

747 



748 William F. Danehower 

2. Such inadequate treatment is worse than no treatment at all, for, 
by suppressing the clinical and serologic manifestations, early diagnosis 
and adequate treatment are prevented. 

3. Penicillin administered four or more years after infection cannot 
change the course of the disease. 

4. The hope of eradicating syphilis lies in ' 'reassigning" its diagnosis 
and treatment to the specialist in dermatology and syphilology, as was the 
case before the advent of penicillin. "The possession of a syringe and a 
bottle of penicillin is not enough." 

If the reconciling of these differing views were simply a matter of 
academic concern, further discussion would be contentious and pointless. 
But there is more at stake here. For it is just possible that within this 
''happenstance" concept there may be hidden, like a pearl within an 
oyster, the clue to the extermination of syphilis. It becomes obligatory, 
therefore, to point out that other syphilologists have presented data that 
are at variance with the views Popper expresses. Let us examine each of 
his four points. 

1. Regarding the question of the inability of "happenstance" peni- 
cillin to cure early syphilis, it seems unlikely that Popper believes that the 
patient with a major illness treated with 600,000 units of penicillin a day 
for eight or ten days would not be cured of concurrent early syphilis. 
Surely this dosage (more than twice the 2.4 million unit minimum effective 
dose recommended for early syphilis) is adequate.^ But there does exist 
room for doubt as to the adequacy of two or three injections of 300,000 
units, given for a coincidental illness of lesser gravity. Nevertheless, the 
investigations of Alexander, Schoch and Mantooth,"^ Rein and Kitchen,^ 
and MerrelP demonstrate that the vast majority of cases of early syphilis 
can be aborted by surprisingly modest doses of penicillin. Merrell's series 
of 7485 patients, tabulated according to the types and amounts of penicillin 
received, indicates that 82 per cent of the cases of primary and secondary 
syphilis treated with as little as 300,000 units remained free of evidence of 
clinical or serologic relapse oyer a post-treatment observation period of 
18 months. As the dosage increased, moreover, the relapse rate declined 
sharply. Had penicillin reached these persons in the incubation period, an 
even better cure rate seems likely. 

2. Anent the statement that "happenstance" treatment is worse than 
no treatment at all, Willcox^ states that the fear of masking syphilis by 
the penicillin treatment of gonorrhea "proved a bugbear." "Either the 
disease was aborted completely, or it declared itself within the usual three 
months. In fact, the disease was usually cured in the incubation period, 
and the enormous decline in the numbers of cases of early syphilis (a fall 
of 95 per cent in the clinics of England and Wales between 1946 and 1956) 
has probably been achieved because of the enormous use of penicillin for 
gonorrhea and other diseases, which cut it off in this way." Delacretaz^ 
concurs: "This notion of arrested syphilis, which seems a widely accepted 



Penicillin Fallout and Infectious Syphilis 749 

one, is based exclusively on disputable observations, as Durel and his 
collaborators have demonstrated." 

3. In the light of the opinions reported in the two preceding para- 
graphs. Popper's third point (that penicillin is ineffective in late latent and 
late syphiUs) ceases to be germane to the discussion. Therefore, the evidence 
to support a contrary view will not be gone into here. 

4. I agree with Doctor Popper that in the treatment of syphilis the 
mere possession of a syringe and a bottle of penicillin is definitely not 
enough. Syphilis is a complicated disease, often difficult of diagnosis, vari- 
able in its course, uncertain as to its outcome. Should I ever contract the 
disease myself, I would hasten to consult my favorite syphilologist, knowing 
that he is best qualified to deal with it, and would wish that every known 
syphilitic was in fact receiving expert care at the hands of a syphilologist. 
Would this be enough? Would this bring us closer to elimination of the 
disease, or even its control? Moore suggests not. ''Never in the history of 
medicine has any infectious disease been eradicated, or its incidence even 
partially controlled, by the sole process of treatment of infected persons."^ 

From 1944 through 1947, the massive assault on syphilis might have 
been expected to exert a profound effect in lowering its incidence. Nearly 
ideal conditions prevailed : 

(a) Throughout the nation there was a vast network of Rapid Treat- 
ment Centers, manned by experts. ^^ 

(6) Record federal appropriations for venereal disease (up to 17 million 
dollars annually) brought treatment within reach of all diagnosed cases, 
and made possible unprecedented epidemiologic activity. ^^ 

(c) Penicillin, then in short supply, was allocated with high priority 
to the venereal disease program, but was not available (in any form prac- 
tical for widespread use) to most of the general physicians throughout the 
country. ^2 

{d) As a result, almost all of the many thousands of cases of diagnosed 
early syphilis were treated by specialists. 

The tremendous good that was accomplished during those four years 
by this gigantic effort stands to the credit of the Public Health Service 
and its co-operating organizations. Nevertheless, despite the cure of thou- 
sands of syphilitics whose disease had been diagnosed early, and despite 
treatment of their known contacts, instead of declining the reported 
incidence of infectious syphilis actually increased by 35 per cent— from 
78,400 cases in 1944 to an all-time high of 106,600 cases in 1947.1^* 

In 1948, the average practicing physician was first able to obtain a 
convenient, practical, "safe" preparation of penicillin with which to load 

* That this increase was actual rather than "statistical" is suggested by the fact 
that the increased reporting and epidemiologic activity required to produce an "epidemic 
of reports rather than of disease" would be expected to bring to light, simultaneously, 
increased numbers of early latent, late latent and late cases previously missed. (These 
normally outnumber early cases by a wide margin.) Instead, there was an actual decrease 
in reported cases in these categories. ^^ 



750 



William F. Danehower 




I950 1955 

FISCAL YEAR 



SOURCE: USPHS VD FACT SHEETS 



Figure 1 



his syringe. ^2 This he employed almost not at all in the treatment of diag- 
nosed syphilis. He did use it generously to treat a vast assortment of 
nonsyphilitic infections, minor as well as major. It is inevitable that many 
an unrecognized early syphilitic, treated for one of these other ailments, had 
his asymptomatic syphilis cured as a side effect. Significantly, it was in 
that same year that the syphilis attack rate began its precipitous 93 per 
cent decline (Fig. 1), 

To be sure, other important factors also were operating during this 
post-war period. Nonetheless, analysis of these trends offers little to sustain 
the premise that the ultimate elimination of infectious syphilis will result 
from treatment (no matter how expert) which is limited to diagnosed cases 
and their known contacts. Too many early infectious syphilitics remain 
(and will continue to remain) undiagnosed, and too many contacts remain 
(and will continue to remain) unidentified, despite the best efforts of public 
and private medicine. 

Heyman,^ very concisely, has stated the reason: ''Infection without 
noticeable lesions probably occurs in a high percentage of cases." These 
persons, and those with the scanty, insignificant primary and banal 
secondary lesions described by Manson and Trice, ^"^ rarely reach a sy phil- 
ologist or any other physician for diagnosis and treatment of early syphilis, 
but they may be fortunate enough to incur some intercurrent illness for 
which peniciUin is administered. Failing such "happenstance" cure, these 
persons remain free to seed their disease to who knows how many others. 
When these undiagnosed — better yet, undiagnosable — cases escape therapy 



Penicillin Fallout and Infectious Syphilis 751 

the incidence curve climbs. When penicillin reaches them, by whatever 
means, the curve falls. 

If we accept ''happenstance" penicillin as the major explanation for 
the decline in the syphilis attack rate in the 1947-1953 period, and lessened 
use of penicillin as the major factor in the recent recrudescence of syphilis, 
one conclusion seems inescapable : Now that physicians, because of human 
reactions and resistance of organisms, are turning from the widespread use 
of peniciUin, opportunity for "happenstance" cure of syphilis is decreasing 
and a continuing rise is expectable. 

In 1956, Pillsbury^^ said: ''It has been assumed by many observers 
that the suppression of syphilis has resulted principally from early diagnosis 
and treatment, the searching out and treatment of infected contacts of 
patients with early syphilis, and adequate follow-up studies to detect 
relapse. That these measures are highly important cannot be doubted. It 
is our belief, however, that the suppression of syphilis has occurred prin- 
cipally as a result of intermittent treatment of the entire population with 
spirocheticidal drugs . . . administered for a variety of reasons, but all 
having as a side effect the suppression of undetected active or latent 
syphilis." Pillsbury further commented: "Concern may be felt, however, 
in regard to the decreasing applicability of penicillin to the general popula- 
tion because of sensitivity induced by repeated administration." 

If these views are correct, and "happenstance" penicillin (rather than 
the public health program) was indeed the real hero of the 1947-1953 
decline in incidence of infectious syphilis, it is of utmost importance that 
this be recognized. The reasons follow. 

1. A blueprint for the eradication of syphilis in the United States is 
outlined in the report of the Surgeon General's Task Force. ^° This plan, 
probably the only practical one possible at this time, calls for a program 
that should result in a further reduction of syphilis mortality and morbidity 
(especially in the late stages). The program is very important and deserves 
the full support of both the profession and the public. Basically, however, 
it is similar to the program carried out since 1937, in that it brings treatment 
only to diagnosed syphilitics and their locatable contacts. It is questionable 
whether any program (no matter how vigorously promoted) that fails to 
bring treatment to the iindiagno sable early syphilitic can carry incidence 
to the vanishing point, as "happenstance" penicillin almost succeeded in 
doing in the early fifties. 

2. If the key to the conquest of syphilis is treatment of the undiag- 
nosed early infectious cases — those in the incubation period, those with 
hidden or atypical lesions overlooked by both patient and physician, those 
too unconcerned to seek diagnosis and treatment — in short, those who 
escape the diagnostic and epidemiologic dragnet, one wonders as to the 
appropriateness of the word "eradication" in this connection. Its Latin 
prefix and stem (e out + radix, radicis, root) suggest the painstaking 
pulling out by the roots of weeds in a garden — weeds that must be iden- 



752 William F. Danehower 

tified as such before they may be plucked. To be sure, there is great value 
in this process, for it maintains a measure of control. But week after week, 
year after year, the process must be repeated, because of the maturing of 
the invisible seeds which were not destroyed in the previous weeding. Were 
it possible, however, to render the soil unfavorable to the growth of the 
seeds, eradication would cease to be necessary. Automatically the result 
would be extermination {ex out + terminus limit, end). 

So it is with syphilis. Great effort is expended to trace down all 
known and suspected cases of syphilis, but, as every experienced epidemi- 
ologist knows, it is an endless task. 

In an article entitled 'The Vicious Chain," Warshofsky^^ recounts the 
experiences of an able venereal disease investigator tracing the chain of 
infection started by a 16 year old boy named Victor. Some 96 teen-agers 
are interviewed. Of these, 18 are found to have syphilis. Undoubtedly 
many others have been spared the disease because of prompt apprehension 
and tr^jatment of these early infectious cases. After almost three months 
of dedicated effort, the public health worker dares to hope that he may 
soon reach the end of the trail. Not so, for with dramatic suddenness the 
track leads back to Victor! Ironically, the chain of infection he started 
has twisted around to reinfect him. And already he has exposed five new 
contacts ! 

What reader of Warshofsky's account can fail to be impressed with 
(1) the tremendous value of the Public Health Program as a means of 
maintaining control of syphilis mortality and morbidity, and, at the same 
time, (2) its Sisyphus-like futility as a means of eliminating the disease 
from the land? 

During those years, however, when the population was fairly saturated 
with penicillin (administered for nonsj'-philitic ailments) the treponeme 
found survival difficult, because its human host was often uninhabitable 
to the organism. Had it been possible, within the space of a few days, to 
have "peniciUinized" every person in the population, syphilis (and perhaps 
a number of other diseases) might have been wiped out almost overnight. 

For many reasons, there is not at the present time any practical way 
of accomplishing a near-simultaneous mass prophylaxis of the entire 
population so as to deprive every treponeme of its every host and potential 
host. Nevertheless, physicians concerned with syphilis control would do 
well to give serious thought now to devising a plan to be put into effect 
promptly when the next safe, convenient, inexpensive spirocheticidal 
remedy is brought forth by the pharmaceutical industry. Such a drug, 
properly distributed, before the population has time to develop allergies to 
it, and before organisms have time to develop resistance against it, could 
conceivably exterminate the great pox — and, simultaneously, by ''happen- 
stance" in reverse, perhaps some other equally important diseases. 



Penicillin Fallout and Infectious Syphilis 753 

acknowledgment 

The very generous help of Dr. Ira Leo Schamberg in the preparation of this paper 
is gratefully acknowledged. 



REFERENCES 

1. Danehower, W. F., Hober, U. M. and Jenkins, B. W.: Penicillin fallout — menace or 

manna? Pennsylvania M. J. 65: 572-573 (May) 1962. 

2. Popper, M.: An answer to "Penicillin Fallout — Menace or Manna?" Pennsylvania 

M. J. 66: 28-29 (April) 1963. 

3. Heyman, A.: Section on Syphilis. In Principles of Internal Medicine. (Harrison 

et al., Eds.). 4th Ed. New York, McGraw-Hill Book Co., 1962, pp. 1078 and 1069. 

4. Alexander, L. J., Schoch, A. G. and Man tooth, W. B.: Abortive treatment of 

syphilis. Am. J. Syph. 33: 429-436 (Sept.) 1949. 

5. Rein, C. R. and Kitchen, D. K.: Mass eradication treatment of treponemal diseases 

with penicillin: Laboratory and clinical basis for selection of effective schedules. 
Am. J. Syph. 37: 37-45 (Jan.) 1953. 

6. Merrell, M.: Estimates of relapse and reinfection rates in early syphilis treated with 

penicillin. Am. J. Syph. 35: 532-543 (Nov.) 1951. 

7. Willcox, R. R.: Reactions to antibiotics — their importance in venereology. Brit. J. 

Ven. Dis. 35: 208-219, 1959. 

8. Delacretaz, J.: International Symposium: Syphilis. Abbottempo /.• 6 (June) 1963. 

9. Moore, J. E.: An evaluation of public health measures for the control of syphilis: 

An epidemiological study. Am. J. Syph. 35: 101 (March) 1951. 

10. Task Force Report: The eradication of syphilis. US Dept HEW p. 9 (March) 1962. 

11. Data furnished by Philadelphia Department of Health, Division of Epidemiology, 

Section on Venereal Disease Control. 

12. Dates of commercial introduction of various forms of penicillin products furnished 

by Smith, Kline and French Laboratories, Philadelphia, Pa. 

13. VD Fact Sheet No. 7, Public Health Service, Table IV, p. 4 (Dec.) 1950. 

14. Manson, R. C. and Trice, E. R.: Changing patterns of syphilis. South. M. J. 56: 

705-710 (July) 1963. 

15. Pillsbury, D. M., Shelley, W. and Kligman, A.: Dermatology, Philadelphia, W. 

B. Saunders Co., 1956, pp. 546-548. 

16. Warshofsky, F.: The vicious chain. Today's Health, Aug., 1963, pp. 24-29. 

5626 North 3rd Street 
Philadelphia 20, Pennsylvania 



V- 



Gonorrhea: Present Knowledge. 
Research and Control Efforts 

JAMES D. THAYER, Ph.D.* 

M. BRITTAIN MOORE, JR., M.D.** 



YESTERDAY 

For such an ancient and prevalent disease, advances in the knowledge 
of gonorrhea have come about very slowly. While medical historians are 
not in agreement,^ it is believed by some that its venereal character was 
known to the early Jews and described in Leviticus XV. Galen in a.d. 130 
was responsible for the name ' 'gonorrhea," meaning ''flow of seed." The 
first description of a contagious urethritis recognizable as the gonorrhea of 
today is recorded in a manuscript in 1376 by John of Arderne, surgeon to 
Richard II and Henry IV. Both Paracelsus, 1530, and John Hunter, 1767, 
believed and taught that gonorrhea was a symptom of syphilis. Hunter's 
strong belief came about after he inoculated himself with gonorrheal pus 
from a patient with concurrent syphilis and developed both diseases. It was 
not until 1860 that Phillippe Ricord unraveled this misconception and 
clearly differentiated these diseases. 

In 1879, long after Anthony van Leeuwenhoek discovered the micro- 
scope, A. Neisser identified the etiologic agent as a diplococcus and named 
it gonococcus. Gram's staining technique in 1884 aided in the microscopic 
presumptive identification of the organism. In 1885, Bumm grew the 
organism on artificial medium and showed that pure cultures, when 
inoculated intraurethrally, could cause the disease. The histopathology of 
the disease was described in 1894 by Finger, Ghon and Schlagenhaufer, 
and the first complement-fixation test was described by Muller and 
Openheim in 1906. 

In 1881, Crede showed that gonococcal ophthalmia neonatorum could 



From the Venereal Disease Research Laboratory, Venereal Disease Branch, Com- 
municable Disease Center, U. S. Public Health Service, Atlanta, Georgia 

* Chief, Antibiotic Surveillance and Methodology Laboratory Research and Develop- 
ment 

** Director 

755 



756 James D. Thayer, M, Brittain Moore, Jr. 

be prevented by routine use of silver nitrate solution in the eyes of the 
newborn. Treatment of gonorrhea with sandalwood oil was discontinued 
when Jonet in 1892 introduced potassium permanganate solution. For 
many years the local application of antiseptics by irrigations and instilla- 
tions was the therapeutic rule. Today, their value is not accepted, and it 
is felt that their use may also have contributed to complications of the 
disease process. 

Almost forgotten in this day of antibiotic and chemotherapeutic 
agents was treatment with vaccines and cultural filtrates. While champi- 
oned by some, they were probably of little value. Domagk's discovery in 
1932 of the curative action of the azo dye, Prontosil, ushered in the era of 
specific chemotherapeutics. At first, the gonococcus succumbed to sulfona- 
mide action but, during the seven years before penicillin became available, 
gonococcal strains developed resistance to concentrations in excess of those 
tolerated by the host.^^ Just when despair was greatest of ever finding a 
substitute for the once successful sulfonamides, penicillin burst forth as 
the almost perfect therapeutic agent. So effective was penicillin in the 
treatment of gonorrhea that competent observers suggested in 1943 that 
160,000 units of penicillin over a 45-hour period represented the use of an 
excessive amount of the drug. 

In a short time, however. Venereal Disease Program statisticians 
pointed out that the reduction in syphilis morbidity noted after 1947 was 
proportionately much greater than that observed in gonorrhea. As early 
syphilis morbidity decreased, public health workers, alarmed by the con- 
tinuing high gonorrhea morbidity, began to devote more time and effort 
to the control of this disease. 

A system known as s'peed zone epidemiology was introduced in Decem- 
ber, 1952 in Washington, D. C. During the next few months, this plan 
went into effect in Memphis, Chicago, Jacksonville, Norfolk, Philadelphia, 
Atlanta, San Francisco, New York City and St. Louis. Male patients with 
gonorrhea were interviewed for relevant contacts, and every effort was 
made to bring the contacts to examination and treatment within 72 hours of 
their being named. Eighty per cent or more of the contacts of male volun- 
teers in most participating clinics were brought to examination and treat- 
ment within the prescribed period. However, the number of male volunteers 
with gonorrheal urethritis attending the clinics remained essentially the 
same. 

In 1956, antibiotic quarantine was combined with speed zone epidemi- 
ology in a report by Hookings and Graves. ^^ Antibiotic quarantine involved 
the use of benzathine penicillin G to maintain prolonged blood levels in an 
effort to prevent reinfection for a period of two to six weeks, depending 
upon the dosage employed. Following this report, speed zone epidemiology 
and antibiotic quarantine were widely applied in major metropolitan area 
venereal disease clinics around the country. Despite enthusiastic applica- 



Gonorrhea: Present Knowledge, Research and Control Efforts 757 

tion for several years in different sections of the country, it became apparent 
that the incidence of gonorrhea was not being significantly reduced. 



TODAY 

Today we have awakened to the realization that even by employing 
the most effective therapeutic agent ever discovered, combined with 
vigorous case-finding efforts, control of gonorrhea has failed. The incidence 
of this disease with little or no immunity and a short incubation period is 
now climbing after a slight decline following the war years. Contributing 
to the total number of cases today is the increased rate among teen-agers. 
A recent national survey of venereal disease cases treated by physicians in 
private practice^ indicates that 70 per cent of the cases are treated outside 
public clinics but only 10 per cent of these cases are reported. The true 
incidence of the disease is unknown, but it is conservatively estimated that 
1.5 million new cases occur annually in the United States. 

Causes of Treatment Failure 

For a decade, it seemed unlikely that the gonococcus would become 
resistant to penicillin as it had to sulfonamides. Long-acting preparations 
of procaine and benzathine salts of penicillin replaced multiple doses of 
sodium penicillin. Prolonged low blood levels from repository preparations 
selectively killed the more highly sensitive strains leaving the less sensitive 
ones to experience growth in residual amounts of penicillin below their 
minimal lethal concentration (MLC). Such penicillin experience known to 
slowly induce resistance in vitro gradually did so in vivo. 

From 1945 to 1954,^ susceptibility studies of 771 cultures of gonococci 
had shown all but five strains to be sensitive to 0,05 u./ml. or less. In 
1955, Thayer et al.^^ in trying to explain the high failure rate of female 
gonorrhea treated with 600,000 units of procaine penicillin in oil with 
aluminum monostearate (PAM) discovered by sensitivity tests of the 
patients' cultures lower susceptibilities than heretofore described. Twenty- 
two per cent of the strains required 0.10 to 0.20 u./ml. to inhibit growth, 
a finding probably related to the failure of penicillin in the dosage used to 
cure the disease. 

Surveillance studies of treatment failure cases since that time have 
shown that the range of penicillin required to prevent in vitro growth is 
slowly expanding over that noted in the early days of penicillin therapy 
and that the greatest proportion of evolving resistant strains is shifting 
within the range toward the higher concentrations. Today some isolates 
require over 1.0 u./ml. to inhibit in vitro growth.^^ 

It is tempting to ascribe penicillin failure to the single fact of increased 
resistance shown by some gonococcal strains, but this would not account 
for other hypotheses or for some known facts. 



758 James D. Thayer, M. Brittain Moore, Jr. 

In considering the successful treatment of gonorrhea, the relationship 
of penicillin blood concentration to the MLC for the infecting gonococcus 
is governed by the time required to effect a bactericidal response at foci of 
infection. In vitro this time has been shown to be 10 to 12 hours exposure 
to kill all but 0.01 per cent or less of the viable cocci. However, 36 hours 
have been required to sterilize the ''persistors" in some cultures. ^^ 

Penicillin blood concentrations developed by individual patients given 
an intramuscular injection of 600,000 units of PAM vary widely. For 98 
patients so treated, concentrations varied from 0.025 to 0.54 u./ml. at 24 
hours, 9 per cent were below 0.10 and 50 per cent below 0.20 u./ml. at 
this time." 

A similar examination by Wright et al.^^ of blood concentrations 
developed by 35 subjects injected with 1.2 mega units of benzathine peni- 
cillin G also showed wide variability. The concentrations at 24 hours for 
these patients varied from an undetectable amount in one patient to a 
maximum of 0.45 u./ml. At this time, 50 per cent of the patients had 
levels below 0.10 u./ml. 

Since gonococci in vitro will survive and multiply in concentrations of 
penicillin below their MLC, it can be seen that the opportunity for survival 
may occur in patients whose blood concentrations are inordinately low. It 
can be supposed that therapeutic failure would then result if other factors 
of host immunity and resistance do not enter the picture. 

It may also be possible that when the gonococcal strain is relatively 
resistant to penicillin — say 0.45 u./ml. — it may be readily killed by the 
excessively high blood concentrations developed by some patients, thus 
resulting in successful therapy and removal of the resistant gonococcal 
strain from the venereal pool. Generally, the more resistant the gonococcal 
strain, the greater likelihood of therapeutic failure. 

Patients harboring strains of gonococci most resistant to penicillin 
have been exposed to prostitutes outside the United States who receive 
low doses of benzathine penicillin at semimonthly intervals as a pro phy- 
lactic measure against syphilis. While this treatment seems effective in 
preventing syphilis and decreases the incidence of symptomatic gonorrhea 
in those treated, the presence of subinhibitory concentrations of penicillin 
in these women undoubtedly contributes to the development of resistance 
with some strains of gonococci.^ 

To eradicate and prevent the further appearance of penicillin-resistant 
gonococci as hypothesized by Garson in 1957® seems today to be an impos- 
sible task. In 1957, a serum concentration of 0.35 u./ml. would have been 
in excess of the highest MLC for any known gonococcal strain in this 
country; today, a blood concentration of 2.0 u./ml. would be needed to 
satisfy the tenets of the hypothesis based on the finding of gonococcal 
strains with MLC's above 1.0 u./ml. 

Apparent treatment failure at times may be due to reinfection when 
the patient returns immediately to his untreated sex partner (s). Failure 



Gonorrhea: Present Knowledge, Research and Control Efforts 759 

may also be falsely ascribed to penicillin when diagnostic methods are not 
used to rule out all possible causes of nongonococcal urethritis. 

Two other possible causes of treatment failure have been put forward. 
The first concerns mistaken diagnosis of the Mima-Herellea group of micro- 
organisms for N. gonorrhoeae. The second is that penicillinase-producing 
bacteria destroy penicillin at foci of infection and thus protect and allow 
gonococci to reinfect the patient. It seems unlikely, however, that these 
hypotheses can account for the major proportion of treatment failure. 

Microscopically, the morphology of the gonococcus and Mimeae organ- 
isms appear quite similar in exudates and from growth on enriched media. 
Differentiation can be easily made on meat extract agar, unenriched broth 
or eosin-methylene blue agar media upon which the gonococcus does not 
grow. Fermentation reactions and other more difficult laboratory proce- 
dures are necessary only to determine species. Where gonococcal fluorescent 
antibody procedures are available, differentiation is rapidly made. Since 
Svihus et SiU^ in 1961 reported a gonorrhea-like syndrome caused by 
Mimeae in Italy, no other outbreak has been reported although Sokoloff 
and Goldstein^i specifically looked for Mima-Herellea organisms in 195 men 
with acute urethritis without finding any. A substantial number of the 
men in the study were military personnel who had been in the Far East or 
Europe. When treated, none of the failure cases was due to Mimeae. The 
authors state that their ''clinical findings correlated with in vitro results: 
No treatment failures were found among patients infected with an organism 
classified as 'sensitive' in vitro; all failures resulted among patients that 
had been classified as 'relatively resistant' by in vitro means." They further 
state, "Our studies, both in vitro and in vivo, support and document the 
opinion that the relative resistance to penicillin N. gonorrhoeae now displays 
is the single causative factor of its frequently reported failure to yield to 
the usual penicillin regimen." 

Unfortunately, Sokoloff did not examine the penicillinase hypothesis 
first suggested by Hagerman^o as the cause of treatment failure in women 
with gonorrheal proctitis. Bang^ could not substantiate the hypothesis as 
it relates to the gram-negative penicillinase-producing bacterial flora of the 
rectum. More recently, Sanders et al.^^ have considered concomitantly 
growing Staphylococcus epidermidis found by them in urethral exudates of 
acute gonorrhea of the male to be more significant in treatment failure 
than relatively penicillin-resistant gonococci. Their laboratory exercise 
showing gonococci growing as satellite colonies around staphylococcal 
colonies composed of billions of penicillinase-producing organisms has 
prompted King^^ to question whether the static agar culture demonstration 
can be representative of the dynamic conditions of the vital process. Huge 
quantities of penicillinase would be required to continually destroy the 
intimacy of circulating penicillin and gonococci at foci of infection. 

Another possible reason for some treatment failure, especially in the 
female, is that gonococci phagocytized by macrophages and columnar 



760 ' James D. Thayer, M. Brittain Moore, Jr. 

epithelium remain viable and protected from extracellular antibiotic. It is 
hypothesized that in time with extrusion of gonococci or dissolution of the 
host cell viable gonococci are available for auto-infection of the host. 
Thayer et al.^^- ^^ have demonstrated the possibility of such an occurrence 
by tissue culture studies; however, clinical research to prove the inference 
has not been tried. 

A significant factor in the failure to control gonorrhea is our inability 
to diagnose the majority of infected females or to bacteriologically deter- 
mine their cure following treatment. Though complications of gonorrhea in 
women — particularly acute and chronic pelvic inflammatory disease — are 
well recognized, clinically the female usually shows few signs and very 
frequently is asymptomatic. Treatment, based on epidemiologic findings 
(contact with an infected male), becomes necessary and acceptable for the 
reason that present laboratory procedures are not rapid enough nor are 
they completely effective in demonstrating gonococci in specimens. Bac- 
teriologic culture procedures performed even under ideal conditions of the 
research laboratory are seldom able to demonstrate gonococci in more than 
50 to 60 per cent of bona fide female contacts. Recent studies by Pariser 
and associates'^ document the existence of asymptomatic male genito- 
urinary tract carriers to compound our problems. That the asymptomatic 
female is capable of disseminating the disease has been proved experi- 
mentally.^ The epidemiologic importance of the infected male with no 
clinical evidence of disease must now be investigated. 

Diagnostic Advances 

An outstanding diagnostic advance is the immunofluorescent method 
for detection and identification of gonococci in exudate. The procedure, 
developed by Deacon et al.^ in 1959, employs an immediate direct fluores- 
cent antibody (FA) method and a delayed FA technique. In the former, 
complete identification as N. gonorrhoeae may be obtained within one hour. 
The delayed FA method, which is more effective for diagnosing the asymp- 
tomatic female, requires a 16- to 20-hour preliminary cultivation of exudate 
to accumulate gonococci in sufficient numbers for detection by fluorescent 
microscopy. The chief advantages of the delayed FA procedure over the 
clinical culture method are the time required to make a definitive diag- 
nosis — 16 to 20 hours against two to ten days — and the greater sensitivity 
of the technique in most laboratories. 

In a field evaluation of the FA method by local public health and 
university laboratories in cooperation with the Venereal Disease Branch, 
Communicable Disease Center,'^ over 85,000 specimens from urethral, 
cervical and vaginal sites of 9483 females were examined. Using immediate 
direct and delayed FA methods and the classical culture method, gonococci 
were detected by culture in 22 per cent, by delayed FA in 37 per cent and 
by direct FA in 15 per cent. When female contacts of known gonorrhea 



Gonorrhea: Present Knowledge, Research and Control Efforts 761 

were studied, the culture was positive in 59 per cent, immediate FA 43 per 
cent and delayed FA in 79 per cent of 1782 patients. 

Much work and study have gone into the development of a serologic 
test so urgently needed for diagnosis of gonorrhea. As yet, however, tests 
are not sufficiently reliable to be used in diagnosis due to poor specificity 
and sensitivity. Brown^ recently reported a complement-fixation test using 
a salt-extracted antigen and found only 35 per cent reactivity among 164 
men with acute gonorrheal urethritis. Among 51 culturally positive females 
in a penal institution, 72.5 per cent were reactive; but, of 189 women 
negative by culture, 40.7 per cent reacted. It would seem that this latter 
group should have been restudied culturally, for Mahoney et al.,^'* in 
studying in 1942 the natural course of the disease in untreated, asympto- 
matic females, found that cultures may spontaneously reverse from positive 
to negative. Furthermore, sporadic positive cultures may appear after a 
relatively long series of negative cultures. Control of gonorrhea will be 
greatly advanced when an adequate serologic test becomes available. 

Recently, Thayer and Martin^^ have described a culture medium with 
selective properties which permits growth of the pathogenic Neisseria 
gonorrhoeae and meningitidis while greatly inhibiting or completely sup- 
pressing saprophytic Neisseria species like sicca, catarrhalis and others. 
The selective medium is prepared by adding 25 u./ml. of polymyxin B 
and 10 meg. /ml. of ristocetin to conventional media. Overgrowth of 
gonococcal colonies by bacterial contaminants encountered in cervical, 
vaginal and rectal specimens is almost totally prevented. The sometimes 
diagnostically confusing Mima polymorpha var. oxidans fails to grow. Thus, 
false positive cultural diagnosis of gonorrhea due to oxidase-positive Mima 
and saprophytic Neisseria, which were infrequently found in genitourinary 
specimens anyway, is almost wholly lacking. Therefore, presumptive testing 
(oxidase positive colonies of gram-negative diplococci) becomes a more 
acceptable diagnostic procedure particularly when large numbers of cul- 
tures must be examined by limited technical personnel. The clinician should 
find the medium helpful in ''test of cure measures" for evaluating thera- 
peutic drugs and drug regimens, especially of the patient who is known to 
have gonococcal proctitis. 

At present, the selective medium is handicapped for rapid gonococcal 
identification in that most strains grow slowly during the first 24 hours, 
not reaching normal-sized colonies until incubated for 48 hours. If this 
difficulty can be overcome, it will be possible to inoculate a culture slant, 
incubate it for 24 hours and mail the culture to a central laboratory for 
identification by FA procedures, thus bypassing lengthy fermentation 
studies. 

The selective medium should be of value in finding the incidence of 
gonorrheal proctitis in the female and the homosexual male. 

In passing, it should be observed that N. meningitidis grows well on 



762 



James D. Thayer, M. Brittain Moore, Jr. 



Table 1. Treatment Results of Uncomplicated Gonorrhea in 
Females Using Currently Recommended Antibiotic Therapy 



The following schedules were rotated weekly in 
participating clinics: 



1. Procaine penicillin G in oil with 2% aluminum 
monostearate (PAM). Single IM injection — 
1,200,000 units. 

2. Benzathine penicillin G. Single IM injection — 
1,200,000 units. 

3. Aqueous procaine penicillin G. Single IM injec- 
tion— 1,200,000 units. 

4. Combination schedule. One injection each of: 
PAM — 600,000 units. Benzathine penicillin G 
— 1,200,000 units. 

5. PAB (preparation containing equal parts aque- 
ous procaine and Benzathine penicillin G). 
Single IM injection— 2,400,000 units. 

6. Streptomycin. Single IM injection — 1 gram. 

7. Tetracycline phosphate — total 500 mg. Two 
IM injections of 250 mg at 24 hour intervals. 

8. Chloramphenicol. Single IM injection — 1 gram 

9. Triacetyloleandomycin (oral) — total 3 grams. 
500 mg. every 4 hours. 

10. Tetracycline (with Amphotericin B) (oral) — 
total 3 grams. 500 mg. every 4 hours. 



NUMBER PERCENTAGE 
COMPLETING COMPLETING NUMBER PERCENTAGE 
TWO-WEEK TWO-WEEK APPARENTLY APPARENTLY 
FOLLOW-UP FOLLOW-UP CURED CURED 



227 


70.7 


145 


63.9 


160 


69.0 


94 


58.8 


130 


69.1 


86 


66.2 



149 



66.8 



82 



55.0 



170 


68.5 


112 


65.9 


197 


70.4 


108 


54.8 


110 


80.3 


82 


74.5 


157 


73.4 


108 


68.8 


154 


70.6 


110 


71.4 


161 


68.8 


128 


79.5 



the Thayer-Martin selective medium and that bacteria for the pharyngeal 
region, including saprophytic Neisseria such as catarrhalis, sicca and others, 
are almost totally inhibited. Tests have shown^^ that many more asymp- 
tomatic meningococcal carriers are discovered by this method and in a 
much shorter time. Typing may be carried out usually with primary iso- 
lates without purification procedures. 

If syphilis were eradicated tomorrow permitting diversion of case- 
finding personnel from this priority area, and we had an adequate serologic 
test for the identification of individuals with asymptomatic disease requir- 
ing treatment ; if it were possible to apply speed zone epidemiology, currently 
recommended antibiotic treatment schedules and selective blood testing, 
it is doubtful that any significant reduction in gonorrhea morbidity would 
occur at this time. One apparent reason for this has been brought home to 
us in a recent cooperative clinical study in which ten antibiotic treatment 
schedules were evaluated in the treatment of the female gonorrhea patient. 
These schedules included the maximum treatments presently recommended 
for uncomplicated gonorrhea in women. Now with an average of 162 
patients completing two-week follow-up on each of the ten schedules, 
failures are noted in 20 to 40 per cent of those treated^^ (gee Table 1). 

It should be mentioned that, while some failures in this study undoubt- 
edly represent reinfections, two-week follow-up in the female is probably 
less than what is required to demonstrate cure, since it is recognized that 
the menses, unusual sexual excitement and other factors can cause the 
female to become at least intermittently infectious again. 



Gonorrhea: Present Knowledge, Research and Control Efforts 763 

A new treatment study designed to overcome this therapeutic deficit 
in women has just begun. The initial phase of the study is in progress now 
in a selected confined group of women in which heterosexual contact— and 
thus reinfection— is virtually impossible. A three-month follow-up period 
is being used to rule out late relapse in the closed study population. 



TOMORROW 

The future, in some respects, looks a good deal brighter than the past. 
The reason for such optimism is due to the recent finding of Kellogg et al.^^ 
from this laboratory that gonococci in culture can be maintained in the 
virulent form. Four morphologically distinct colonial types have been 
observed in culture. Type 1 is of most interest as it is found only in the 
purulent exudate from acute gonorrhea of the male. Other types appear 
when unselected subculturing of the primary isolate occurs and are prob- 
ably due to the genetic instability of the type 1 cells in vitro. After 69 
passages on suitable culture media, type 4 cells, typical of so-called ''labora- 
tory strains," were no longer virulent. It is with such cultures that experi- 
mental studies in serodiagnosis^^ and immunity^^ have been performed in 
the past. On the other hand, type 1 cells, after 69 selected subcultures, 
retained virulence and infected male volunteers, producing typical gonor- 
rheal signs and symptoms. 

The use of virulent cultures in experimental studies promises to 
advance our knowledge of gonorrhea over anything previously known and 
may make it possible to control the disease. 

It is conceivable that study of antigenic fractions of the type 1 organ- 
ism will lead to skin-testing antigens. Already, a protein fraction has been 
isolated for serologic precipitation reactions that have good specificity.^^ 
Such a test would be of great value in epidemiological surveys. Serologic 
grouping of gonococci may become possible and differences discovered in 
gonococci isolated from symptomatic and asymptomatic cases. Physio- 
logical and biochemical studies of the virulent organism may reveal 
metabolic pathways that will lead to better diagnostic media. 

It will be possible under controlled conditions to study results of 
therapy in human volunteers using type 1 strains of known antibiotic 
sensitivity to infect the subjects. The interaction of serum antibiotic 
concentration, gonococcal susceptibility to antibiotic, excretion rate, etc., 
can be observed and related to failure to cure the disease. 

The ultimate finding, of course, would be the discovery of an immu- 
nizing antigen for use in preventive vaccination. The finding and applica- 
tion of such an immunizing agent, together with specific therapy, would 
satisfy the basic tenets of communicable disease management and open the 
door to an adequate gonorrheal control program. 



764 James D. Thayer, M. Brittain Moore, Jr. 

REFERENCES 

1. Bang, J.: Demonstration of gonococci in rectal cultures. Acta dermato.-venereol. 84: 

4-10, 1954. 

2. Brown, B. C: The serodiagnosis of gonorrhea utilizing a new antigen. J. Clin. & 

Lab. Invest. In press. 

3. Brown, L., Copeloff, M. B. and Peacock, W. L., Jr.: Study of gonorrhea in treated 

and untreated asymptomatic women as determined by fluorescent antibody and 
culture methods. II. Teen-age and young adults confined. Am. J. Obst. & Gynec. 
84: 753-757 (Sept. 15) 1962. 

4. Curtis, A. C: National survey of venereal disease treatment. J. A.M. A. 186 (1): 

46-49, Oct. 5, 1963. 

5. Deacon, W. E., Peacock, W. L., Jr., Freeman, E. M. and Harris, A.: Identification 

of N. gonorrhoeae by means of fluorescent antibodies. Proc. Soc. Exper. Biol. & 
Med. 101:322-^25, 1959. 

6. Garson, W.: Evaluation of gonorrheal therapy. Presented at USPHS Venereal Dis- 

ease Seminar, Regions I, II, V and VI, Detroit, Mich., Feb. 20, 1957. (DHEW, 
PHS, CDC, Atlanta, Ga. mimeo.: 1-7, Mar. 1957). 

7. Garson, W. and Thayer, J. D.: Gonococcus. In Bacterial and Mycotic Infections of 

Man, 3rd Ed., Chap. 25 (R. J. Dubos, Ed.). Philadelphia, J. B. Lippincott Co., 
1958. 

8. Gillespie, E. J. and Thayer, J. D.: Surveillance studies of A^. gonorrhoeae resistance 

to penicillin. Western Branch A.P.H.A., Phoenix, Ariz., May 25-30, 1963. (DHEW, 
PHS, CDC, Atlanta, Ga.). 

9. Guthe, T.: Failure to control gonorrhoea. Bull. World Health Org. 24: 297-306, 

1961. 

10. Hagerman, G.: On the factors causing recurrence after penicillin treatment of 

gonorrhea. Acta dermato.-venereol. 28: 362-370, 1948. 

11. Hookings, C. E. and Graves, L. M.: Benzathine penicillin G in the control of 

gonorrhoea. Brit. J. Ven. Dis. 33: 40-42, 1957. 

12. Kellogg, D. S., Jr., Peacock, W. L., Jr., Deacon, W. E., Brown, L. and Pirkle, C. I.: 

Neisseria gonorrhoeae. I. Virulence genetically linked to clonal variation. J. Bact. 
85: 1275-1279, 1963. 

13. King, A. J.: Penicillin resistance in gonorrhoea. Brit. J. Ven. Dis. 36: 34-35, 1960. 

14. Mahoney, J. F., VanSlyke, C. J., Wolcott, R. R., Thayer, J. D. and Nimelman, A.: 

Culture studies in chronic gonorrhea of women. Am. J. Syph., Conor. & Ven. Dis. 
26: 38-47, 1942. 

15. Mahoney, J. F., VanSlyke, C. J., Cutler, J. C. and Blum, H. L.: Experimental 

gonococcic urethritis in human volunteers. Am. J. Syph., Conor. & Vener. Dis. 30: 
1-39, 1946. 

16. Pariser, H., Farmer, A. D., Jr. and Marino, A. F.: Asymptomatic gonorrhea in the 

male. Presented at the 14th Annual Symposium on Recent Advances in the Study 
of Veneral Diseases, Houston, Tex., Jan. 24-25, 1964. 

17. Price, E. V.: Field evaluation of fluorescent antibody technique in diagnosis of 

gonorrhea in the female. Presented at the 14th Annual Symposium on Recent 
Advances in the Study of Venereal Diseases, Houston, Tex., Jan. 24-25, 1964. 

18. Price, I. N. O.: Gonococcal complement-fixation test. J. Path. & Bact. 33: 493,1930 

19. Reising, G. and Kellogg, D. S., Jr.: A proposed precipitin test for the detection of 

gonococcal antibodies. Presented at the Annual Meeting of the Southeastern 
Branch of the American Society for Microbiology, Jacksonville, Fla., Oct. 18-19, 
1963. 

20. Sanders, A. C, Pelczar, M. J., Jr. and Hoefling, A. F.: Interaction of staphylococcus 

and N. gonorrhoeae in "penicillin resistant" gonorrhea. Antibiot. & Chemother. 7: 
10-16, 1961. 

21. Sokoloff, B. and Goldstein, H.: Clinicolaboratory study of acute gonorrhea in men 

in the El Paso, Texas area. J.A.M.A. 184: 197-200, 1963. 

22. Svihus, R. H., Lucero, E. M., Mikolajezyk, M. T. and Carter, E. E.: Gonorrhea- 

like syndrome caused by penicillin-resistant Mimeae. J.A.M.A. 177: 121-124, 1961. 

23. Thayer, J. D., Perry, M. I., Field, F. W. and Garson, W.: Failure of penicillin, 



Gonorrhea: Present Knowledge, Research and Control Efforts 765 

chloramphenicol, erythromycin and novobiocin to kill phagocytized gonococci in 
tissue culture. Antibiotics Annual. New York, Medical Encyclopedia, Inc., 1956-- 
1957, pp. 513-517. 

24. Thayer, J. D., Perry, M. I., Magnuson, H. J. and Garson, W.: Failure of penicillin 

to kill phagocytized A'', gonorrhoeae in tissue culture. Antibiot. & Chemother. 7: 
311-314, 1957. 

25. Thayer, J. D., Field, F. W., Magnuson, H. J. and Garson, W.: Sensitivity of gono- 

cocci to penicillin and its relation to "penicillin failures". Antibiot. & Chemother. 
7: 306-310, 1957. 

26. Thayer, J. D., Field, F. W. and Garson, W.: In vitro susceptibility of A^. gonorrhoeae 

to the action of sulfamethoxypyridazine (Kynex) and sulfadiazine. Antibiot. & 
Chemother. 9: 176-179, 1959. 

27. Thayer, J. D., Field, F. W., Perry, M. I., Martin, J. E., Jr. and Garson, W.: Surveil- 

lance studies of N. gonorrhoeae sensitivity to penicillin and nine other antibiotics. 
Bull. World Health Org. 24: 327-331, 1961. 

28. Thayer, J. D., Martin, J. E., Jr. and Field, F. W.: Results of Neisseria gonorrhoeae 

surveillance study. Presented at the XII International Congress of Dermatology, 
Washington, D. C, Sept., 1962. Internat. Congress Series No. 55, Excerpta 
Medica Foundation, New York, 1963, pp. 924-925 

29. Thayer, J. D. and Martin, J. E., Jr.: A selective medium for the cultivation of N. 

gonorrhoeae and A^. meningitidis. Pub. Health Rep. 79 (1): 49-57 (Jan.) 1964. 

30. Thayer, J. D., Frank, P., Martin, J. E., Jr. and Miller, L.: A selective medium for 

the cultivation of N. meningitidis from the carrier state. Preliminary report. 
(In preparation.) 

31. Wright, W. W., Welch, H., Wilner, J. and Roberts, E. F.: Body fluid concentra- 

tions of penicillin following penicillin G. Antibiot. Med. & Clin. Ther. 6: 232-241, 
1959. 

32. Unpublished data from Venereal Disease Branch, Communicable Disease Center. 

Communicable Disease Center 
U. S. Public Health Service 
Atlanta, Georgia 



Gonorrhea and Nonspecific Urethritis 



KYRIL B. CONGER, M.D.* 



The gonococcus resembles the rat. Despite major efforts to 
eradicate it from our society by enlightened epidemiological control, 
modern diagnostic methods and new antibiotics, it has continued to 
flourish. In remarks made to the World Health Organization, Dr. Thorstein 
Guthe said that no method as yet has been found of ''catching up with this 
heel-less Achilles." 



INCIDENCE 

It has been estimated that the incidence of gonorrhea in this country 
is over one and one-half million cases per year, 80 per cent of these being 
unreported.^ A disturbing aspect of this is the steady increase of the gonor- 
rhea rate in this and other countries. Of the 105 countries participating in 
the study by the World Health Organization, 71 per cent showed a rising 
trend in the disease rate. No figures are available on the incidence of 
nonspecific urethritis, a disease with comparable morbidity. 

Contributing Factors 

Various factors have been suggested as contributing to the dismal 
failure of our modern society to suppress or control gonorrhea. 

1. Public attitudes. The general concept among the laity about gonor- 
rhea is an indifferent one. It is thought by many to be a trifling affliction 
which can be cured by one visit to the drugstore, and which, in truth, is 
no worse than a bad cold. In the public health field, on the other hand, 
insurmountable problems in control of the disease have resulted in a 
defeatist attitude. Today nearly all funds for venereal disease control are 
earmarked for the eradication of syphilis, a disease which is easily detect- 
able, and which responds predictably to treatment, and whose contacts are 



Read at the Symposium on Venereal Disease, the 112th Annual Meeting of the American 
Medical Association, June 20, 1963, Atlantic City, New Jersey 

* Professor of Urology, Temple University School of Medicine, Philadelphia, Pennsyl- 
vania. 

767 



768 Kyril B. Conger 

readily traceable. The admitted failure in the control of gonorrhea has 
lessened the interest of public health authorities in this area. 

2. The inability to diagnose gonorrhea in the female is another formi- 
dable obstacle in the control of the disease. The lack of efficient diagnostic 
procedures, and the usual absence of symptoms in women, result in the 
female serving as a chronic reservoir of disease. Ordinary smears and 
cultures are usually valueless, and the recently developed fluorescent 
antibody technique has at least a 20 per cent incidence of false negative 
results. 

3. An obvious reason for the increase in gonorrhea lies in the emergence 
of antibiotic-resistant strains. As time progresses, we might expect that 
penicillin and broad-spectrum resistant gonococci will multiply and dissem- 
inate more rapidly than the tractable strains. 

4. The treatment of gonorrhea by unqualified personnel sharply decreases 
the chances of its control. A patient treated by a druggist has no laboratory 
confirmation of the diagnosis or cure, while the pharmacist himself has no 
interest in, or responsibility for, the identification and treatment of the 
contact. Years ago, the physician treated all cases of urethritis; today the 
vast majority of his patients represent penicillin-resistant cases, who come 
to him because self-treatment has failed. 

5. The extremely short incubation period of the disease (three to seven 
days) makes it possible for gonorrhea to be spread more rapidly than 
contacts can be followed up and treated. This, together with the difficulty 
in diagnosis in the female, presents a formidable problem. 

6. Public health aspects of nonspecific urethritis. Little is known of the 
epidemiology of nongonorrheal urethritis. This is because it is a convenient 
term for a number of various entities which may or may not be acquired 
through sexual exposure. It includes atypical cases of gonorrhea seen after 
treatment, as well as patients with Reiter's disease, abacterial pyuria, 
urethral stricture, chemical urethritis, trichomoniasis and chronic prosta- 
titis. 

Nonspecific urethral discharge is a symptom of a disease rather than 
a specific disease entity. The public attitude toward this disease has 
always been indifferent because it does not carry the social stigma which 
accompanies gonorrhea. In the armed forces, individuals suffering from 
nonspecific urethritis, and their organizational units, are not subject to 
the same disciplinary measures imposed when the urethritis is caused by 
the gonococcus, although transmission may be by the same sexual route. 
Nevertheless, nonspecific urethritis is often more difficult to treat than 
gonorrheal urethritis. 



THE CLINICAL COURSE OF GONORRHEA 

Signs and Symptoms. In the male, gonorrhea follows a typical course. 



Gonorrhea and Nonspecific Urethritis 769 

Three to seven days after exposure, a purulent discharge begins, which is 
diffuse, and accompanied by urethral edema. Treatment with antibiotics 
usually brings about prompt disappearance within 24 hours, unless the 
organism is resistant to the drug. In women, the disease may be completely 
without symptoms, although the cervix, vagina, Skene's and Bartholin's 
glands as well as the urethra are infected. Treatment, again, is with anti- 
biotics, which should be continued until the gonococcal organisms cannot 
be demonstrated in the urethra, cervical canal or periurethral glands. 
Complications in women are more serious than in men, and include the 
whole gamut of pelvic inflammatory diseases. Throughout the entire course, 
diagnosis is difficult and demonstration of the gonococcus by laboratory 
methods is inconsistent. Fluorescent antibody examination of material 
taken from the urethra and cervix is the most reliable method of identifi- 
cation. 

Diagnosis and Treatment, In the male, diagnosis is simple. A gram 
stain of the urethral discharge reveals large numbers of gram-negative 
intracellular diplococci. Cultures will show Neisseria gonorrhoeae. In women, 
the diagnosis is more difficult and must be obtained by examining the 
material from the urethra, periurethral glands and cervix with the fluores- 
cent antibody technique. Even with this method many cases will be missed. 

Male patients are immediately and dramatically cured, if the gono- 
coccus is penicillin-sensitive, by a single injection of 1,200,000 units of 
penicillin intramuscularly. The discharge should stop in 24 hours and all 
subsequent examinations by culture or the fluorescent antibody technique 
will be negative. If the discharge does not stop, and the gonococci persist 
in it, another type of antibiotic should be tried. This includes most of the 
broad-spectrum antibiotics including tetracycline, oxytetracycline (Terra- 
mycin), chlortetracycline (Aureomycin), and chloramphenicol (Chloro- 
mycetin). The dosage should be high, employing 500 mg. every six hours 
for a total of five days. After a five-day rest period, if the discharge is still 
present, another type of antibiotic may be used for another five-day course. 

Test for cure in the male is simple. After a month has passed without 
urethral discharge, and pus cells and bacteria are absent from the voided 
urine, the patient is cured. In women, the criterion for cure consists of 
multiple successive negative examinations for the gonococcus in the urethra 
and cervical canal by the fluorescent antibody technique. 

Treatment of Antibiotic-Resistant Cases. No new or spectacular ther- 
apy is available for treatment of patients failing to respond to penicillin or 
the other antibiotics. Such patients must be followed carefully with 
courses of various antibiotics at weekly intervals, with frequent tests by 
culture and sensitivity studies to see if new organisms are present. Patients 
should receive the benefit of a hygienic regimen, with adequate periods of 
rest, exercise, freedom from sexual excitement and the interdiction of 
alcohol and spicy foods. However, the patient likely to get venereal disease 
frequently resists a hygienic regimen. 



770 Kyril B. Conger 

THE CLINICAL COURSE OF NONSPECIFIC URETHRITIS 

Signs and Symptoms. The incubation period of nonspecific urethritis 
is not typical. Instead of a fixed incubation period of three to seven days, a 
nonspecific discharge may appear 24 hours to several months after exposure. 
There may or may not be a history of sexual contact. Many cases of non- 
specific urethritis result from a metastatic prostatitis, infected by an upper 
respiratory infection. 

The urethral discharge is usually mucoid and scanty rather than 
purulent and diffuse, and may only exist as a morning drop, which has 
accumulated during the night without urination. 

Diagnosis, Diagnosis of nonspecific urethritis is made by microscopic 
examination of the urethral discharge. The absence of gram-negative intra- 
cellular diplococci by any of the three laboratory methods confirms the 
presence of nongonorrheal (nonspecific) urethritis. Various types of organ- 
isms, or none at all, may be found. The most common type of pyogens 
are staphylococci, coliform organisms, miscellaneous cocci and diphtheroids. 

Treatment. Penicillin is of little value in the treatment of non- 
specific urethritis. A culture of the urethral discharge with sensitivity 
studies should be made and treatment carried out with the appropriate 
antibiotic. This includes nearly all of the broad-spectrum group. Patients 
with nonspecific urethritis should also observe a health regimen similar to 
that advised in the treatment of gonorrhea, and avoid alcohol and highly 
seasoned foods. If the discharge persists over four weeks, complete uro- 
logical studies should be carried out to determine the cause of the chronicity. 



TRICHOMONAS VAGINALIS URETHRITIS 

Signs and Symptoms. Patients with trichomoniasis may have no 
symptoms at all except a slight urethral discharge accompanied by itching 
and a mild dysuria. It is a chronic low grade infection which does not 
ordinarily respond to any type of antibiotic therapy. 

Diagnosis. Diagnosis of this infestation is made by examination of 
the urethral discharge suspended in saline solution. A typical trichomonad, 
which is the size of a white blood cell, will be seen. This protozoan may be 
found in a wet suspension of prostatic fluid. If no urethral discharge is 
present, a centrifuged urine sediment, examined wet, may also reveal the 
organism. 

Treatment. The drug metronidazole (Flagyl)^ appears to be specific 
in destroying this protozoan. The dosage is 250 mg. given orally, twice 
daily for a period of one to two weeks. Since the source of the infection is 
in the marital partner, the wife as well as the husband should be treated 
with this medication. A high percentage of cure (85 per cent) has been 
reported by this method. It is probable that failure is due to reinfection or 
extramarital exposure. 



t 



Gonorrhea and Nonspecific Urethritis 771 

REITER'S DISEASE 

Signs and Symptoms. The triad of chronic urethritis associated with 
conjunctivitis and poly migratory arthritis has been well known ever since 
Reiter's original description in 1916. Little has been learned about it since 
then. The conjunctivitis may be followed by iritis and keratitis. The 
disease is accompanied by low grade fever, leukocytosis, and an increased 
sedimentation rate. Remissions and exacerbations may occur. 

Diagnosis. Diagnosis is made by the typical history and findings of 
urethritis, conjunctivitis and arthritis. There are no specific diagnostic 
tests available. The finding of pleuropneumonia-Uke organisms ('TPLO") 
are probably of incidental significance only, as these bacteria are normal 
inhabitants of the urinary tract. It is probable that this disease is caused 
by a virus, as yet unidentified. 

Treatment. There is no specific treatment. Instead, various courses of 
broad-spectrum antibiotics are given empirically and supportive and 
symptomatic treatment carried out. 



TREATMENT OF THE CHRONIC URETHRAL DISCHARGE 

Neither the patient nor the physician need be concerned about a 
nonspecific urethral discharge until it becomes chronic. After it has sur- 
vived four weeks of therapy with various antibiotics, it may be classified as 
a urological problem and complete urological investigation made to deter- 
mine the cause of its chronicity. The common causes of refractory urethritis, 
and their management follow: 

1. Urethral Stricture. This is the most common cause of persistent 
urethral discharge. It is seen in patients who have had previous attacks of 
urethritis with inflammatory or iatrogenic strictures. The stricture is both 
diagnosed and treated by the gentle passage of a No. 24 to No. 26 F. steel 
sound through the urethra under local anesthesia and aseptic conditions. 
The discovery and periodic dilatation of this stricture will result in the 
prompt disappearance of the discharge. 

2. Overtreatment. Since local therapy was virtually abandoned in 
favor of antibiotic therapy, overtreatment is infrequently seen. However, 
occasionally patients are observed who have been treated by frequent 
instillations of medications into the urethra, or by instrumentation. These 
maneuvers, instead of ablating the infection, may cause a traumatic or 
chemical form of urethritis, which keeps the discharge active. 

3. Balanoposthitis. A long foreskin, associated with inflammatory 
changes, frequently causes a urethral discharge. If attempts at hygienic 
treatment are unsatisfactory, a circumcision should be carried out. 

4. Chronic Prostatitis. This is a common cause of chronic urethritis. 
It is uncertain as to whether prostatic massage is of any benefit except as 
a diagnostic measure; i.e., to obtain prostatic fluid for examination, cell 
count and culture. The prostate gland may be emptied much more effica- 



772 Kyril B. Conger 

ciously by sexual intercourse, and this should be advised if the patient has 
refrained from intercourse due to interdiction by his physician. Culture and 
sensitivity studies of the prostatic fluid, with treatment b}^ the appropriate 
antibiotic is indicated. Hot sitz baths also help. 

5. The Use of Alcohol. Many patients develop a urethral discharge 
simply as a result of the overuse of alcohol with excretion of alcohol and its 
congeners in the urine. A period of strict teetotalism will cure such a 
urethritis. 

6. Recurrent Infection. A patient who frequently exposes himself to 
his previous sexual contacts, or to new ones, will obviously suffer reinfection 
of the urethra. Surprisingly enough, the patient may not find it important 
enough to tell his physician about his new experiences. 

7. The Neurotic Patient. Many patients keep a urethritis active by 
continually stripping the urethra to see if any discharge is present. The 
mechanical irritation resulting from this maneuver, if it is persisted in 
until mucus is expressed, is sufficient to keep a chronic urethritis going. 
Because of the high emotional investiture in the genital organs, there is a 
high incidence of psychic overlay in symptoms resulting from a mild 
urethral discharge. Such patients must have much reassurance that the 
urethritis will not affect their future health or fertility, and should be 
advised against stripping the urethra to see if discharge is present. 



HOW MAY GONORRHEA BE CONTROLLED EFFECTIVELY? 

The admitted failure of public health authorities to control gonorrhea 
has been mentioned. Many of them feel that all efforts will continue to be 
futile until a vaccine is found to cure the disease'' or until a serologic test 
is developed to make immediate diagnosis possible. ^ Thus, the most 
formidable attack on the disease would result from the development of 
better diagnostic tools and improved medication. Research funds should 
be provided to medical centers to encourage the development of better 
diagnostic tests, particularly in the female, and to further bacteriological 
and clinical work in the production of new antibiotics and chemotherapeutic 
agents for treatment of the antibiotic-resistant strains of gonorrhea. 



REFERENCES 

1. Council on Drugs: Metronidazole (Flagyl) J.A.M.A. 183: 11, 144, 1963. 

2. Lentz, J. W. : Venereal disease control in the 20th century. Nursing Outlook, Vol. 10, 

Nov., 1962. 

3. Simpson, W. G. and Brown, W. J.: Current status of the diagnosis and management 

of gonorrhea. J.A.M.A. 182: 63, 1962. 

4. World Health Organization Report, 1963. 

5. Gonococcus: Procedures for Isolation and Identification. U. S. Department of 

Health, Education and Welfare, Public Health Service Publication No. 499, 1961. 

3401 North Broad Street 
Philadelphia 40, Pennsylvania 



The Gynecological Lesions of 
Lymphogranuloma Venereum and 
Granuloma Inguinale 

D, B. STEWART, M.D., F.R.C.S.(C), F.R.C.O.G.* 



These two quite distinct diseases are often confused with each 
other. They have been given similar names, and also they often occur in 
the same areas, among the same sort of people, and sometimes even in the 
same patient. This account, based on observations made by our group in 
Jamaica, gives some of the present ideas about these conditions. 

Lymphogranuloma venereum is caused by a virus. The diagnosis can 
be aided, though not completely confirmed, by the Frei intradermal skin 
test or the lymphogranuloma venereum complement fixation test. The 
former gives about 20 per cent false negative results, and the latter is often 
found to be positive in people who show no signs of the disease. Isolation 
of the virus from active lesions is conclusive, but difficult and expensive. 

Granuloma inguinale is caused by a microbacillus called Donovania 
granulomatis. This has been isolated from the lesions, grown in culture, 
and subcultured; but so far the disease has never been produced in volun- 
teers by infecting them with organisms from cultures, so Koch's postulates 
are not completely satisfied. The Donovan bodies can be seen, mainly in 
large mononuclear cells, in stained smears of diseased tissue. A complement 
fixation test is under trial. 

The usual clinical features of the two diseases are compared in Table 1. 

Lymphogranuloma venereum infections behave differently in the two 
sexes. Evanescent primary ulcers of the genitalia have been described in 
men, but we have never recognized them in women. Inguinal buboes are 
common in men; uncommon in women: but the reverse is true of rectal 
lesions. The reasons for these differences are obscure. The disease seems to 
be commoner, or at least to be recognized more often, in men than in 



Read at the Symposium on Venereal Disease, the 112th Annual Meeting of the American 

Medical Association, June 20, 1963, Atlantic City, New Jersey 
* Professor of Obstetrics and Gynaecology, University of the West Indies, Jamaica 

773 



774 D. B. Stewart 

Table 1. Comparison oj Clinical Features 

LYMPHOGRANULOMA VENEREUM GRANULOMA INGUINALE 

Primary ulcer (?) Flat raised papule 

Chronic ulceration with tissue destruction Chronic granulomatous ulceration 

Inguinal buboes (men > women) Secondary inguinal adenitis 

Proctocolitis and strictures (women > men) Rectal ulcers (rare) 

Soft swelling of labia /clitoris Genital "elephantiasis" 



women. In Jamaican clinics the number of new male cases is about four 
times the number of female cases (Douglas, 1962). 

The skin lesions of granuloma inguinale tend to spread and coalesce, 
but seldom cause destruction of deep tissue unless there is heavy secondary 
infection. Secondary inguinal adenitis may be mistaken for true buboes. 
Rectal lesions are uncommon. Massive ''elephantiasis" of the genitalia is 
a late manifestation. This disease is slightly more common in women than 
in men. 



LYMPHOGRANULOMA VENEREUM 

The usual manifestations of this disease in women are listed in Table 2. 

Buboes, when they occur, seem to be an early phase of the infection. 
The incubation period is difficult to assess, but it is probably one to four 
weeks. Usually the patient complains of fever, headache, nausea and 
muscle pains. Lymph nodes both above and below the inguinal ligament 
become matted together, swollen and painful. They are firm and rubbery 

Table 2. Common Manifestations of Lymphogranuloma Venereum in Women 

Buboes (early, rare) 

Vulvar Lesions 

Urethra — Stricture or loss 

Labia — Notching or fenestration: 'Tuffy swelling" 

Vagina — Stenosis 

Occasional secondary prolapse 

Rectal Lesions 
Proctocolitis 
Stricture 
Fistula 
Distortion of sphincter 



Lesions of Lymphogranuloma Venereum and Granuloma Inguinale 775 

at first and later become fluctuant. The overlying skin turns a dusky 
purple and becomes adherent to the underlying mass, then breaks down 
into multiple sinuses. These heal slowly, leaving characteristic puckered 
linear scars. Recent buboes resolve quickly under treatment with sulfon- 
amides or tetracycline. If they are fluctuant, the pus should be aspirated 
with a wide-bore needle introduced through healthy skin. This may prevent 
sinus formation. 

Lesions of the vulva and vagina cause destruction of tissue, or dense 
fibrosis and stricture formation, or both. The process seems to begin with 
ulceration, often at the fourchette, on the labia minora, or beside the 
urethral meatus. There may be definite ulcers with a yellowish base, or 
merely red patches looking like abrasions of the skin with a little under- 
lying edema. The ulcers are almost painless and are only slightly tender, 
so the patient may not notice them or may not think them worthy of 
consultation with a doctor (Fig. 1). 

Insidiously, the ulcers progress to destroy underlying tissue. If they 
are on the labia, these become notched or fenestrated (Figs. 2 and 3). We 
think that ''button-holed labia" are almost certain evidence of lympho- 
granuloma venereum. If the ulcers are at the urethra, this is gradually 
destroyed from below upward and so progressively shortened (Fig. 4). 
Control of urination is not lost unless the upper quarter-inch of the urethra 




Figure 1. Early ulcer of lymphogranuloma venereum situated at the fourchette 
(see also Plate VI). It was painless and was discovered accidentally. (Stewart, D. B. in: 
Lymphogranuloma Venereum. Edited by M. M. Sigel, Univ. Miami Press, 1962.) 



776 



D. B. Stewart 



Figure 2. A punched-out early 
destructive ulcer of lymphogranu- 
loma venereum on the labium 
minus. 




Figure 3. Multiple fenestration of the labium minus due to old lymphogranuloma 
venereum. The urethra was also destroyed. 



Lesions of Lymphogranuloma Venereum and Granuloma Inguinale 777 

is destroyed. Sometimes this part is spared but becomes fibrosed and 
narrowed, causing difficulty in micturition or even retention of urine. The 
opening of the bladder is found up behind the symphysis, where it may be 
distorted or concealed by tags of vaginal skin. Below this is a flat skin 
surface, perhaps with a few remaining tags to indicate where the urethra 
used to be (Fig. 5). 

This process can be stopped by chemotherapy if it is detected in time, 
but if the whole urethra has been destroyed it is most difficult to restore 
continence. A new urethra can be constructed, but it is seldom possible to 
provide it with a competent sphincter. This is one of the most difficult 
problems in gynecological surgery. 

Sometimes the vagina becomes fibrous and stenosed. Usually this 
begins at the vault: the cervix is concealed and the vagina is gradually 
shortened and obliterated. Occasionally the stenosis occurs near the introi- 
tus, and we have seen a multipara whose lower vagina closed completely 
over a period of less than four months, producing cryptomenorrhea 
(Fig. 6). 

In some cases there is moderate soft swelling of the labia or clitoris. 
This is haphazard in its distribution and does not appear to be related to 
lymphatic obstruction. Massive hypertrophy with ulceration, the so-called 
"esthiomene," has been described as a characteristic of lymphogranuloma 
venereum. We do not think this is so. 

Rectal lesions may occur alone or may be associated with lesions of 
the vulva, but for some reason they rarely occur in patients with buboes. 
The process begins as an acute purulent proctocolitis. The patient com- 



Figure 4. Partial destruction 
of the urethra due to lympho- 
granuloma venereum (see also 
Plate VI). The site of the ex- 
ternal urethral meatvis is at (A), 
and the opening of the remaining 
upper part of the urethra at (B). 
The patient was still continent 
of urine. (Stewart, D. B. in: 
Lymphogranuloma Venereum. 
Edited by M. M. Sigel, Univ. 
Miami Press, 1962.) 




778 



D. B. Stewart 




Figure 5. Complete destruction 
of the urethra. The catheter shows 
the hole in the bladder base. 
(Lawson and Stewart: Obstetrics 
and Gynaecology in the Tropics. 
In Press.) 



1 




Figure 6. Stenosis of the vagina 
and partial destruction of the 
urethra due to lymphogranuloma 
venereum. The probe points to the 
obliterated vagina; the arrow indi- 
cates the scarred opening of the re- 
maining portion of the urethra. 
(Stewart, D. B.: Lymphogranuloma 
Venereum. Edited by M. M. Sigel, 
Univ. Miami Press, 1962.). 



Lesions of Lymphogranuloma Venereum and Granuloma Inguinale 779 

plains of passing blood, mucus and pus; there is tenesmus, alternating 
constipation and diarrhea, rectal pain, pyrexia and weight loss. Edematous 
perianal tags are often found (Fig. 7). The mucosa of the anal canal and 
rectum is rough and granular and the wall of the affected gut is thick and 
rigid. Characteristically these changes are usually most severe about 5 cm. 
from the anal margin, but they may extend as high as the pelvic colon. 

Early treatment is important, as only about one-tenth of adequately 
treated cases develop strictures. It consists of rest and low residue diet 
plus tetracycline or streptomycin, which seem more effective than sulfona- 
mides. It is not known whether improvement results from control of the 
virus or of the secondary bacterial infection. 

Rectal strictures may develop within a few months after the initial 
proctocolitis, but sometimes not for several years. The most common 
symptom is increasing constipation and the passage of thin pencil-like 
stools with mucus, blood and pus. The stricture may be annular or tubelike, 
and there may be several strictures with relatively normal bowel between. 
The lowest edge of the stricture is usually about 4 or 5 cm. from the anal 
margin. Repeated straining at stool may result in uterovaginal prolapse 
(Fig. 8). 

Distortion and incompetence of the anal sphincter is often associated 
with rectal stricture. It is not known whether this is caused directly by 
infection and fibrosis of the muscle or indirectly by interference with its 



I 



Figure 7. Acute proctocolitis, 
with pus pouring through the dis- 
torted and incompetent anal sphinc- 
ter. The patient was a virgin aged 
17. (Lawson and Stewart: Obstetrics 
and Gynaecology in the Tropics. 
In Press.) 




780 



D. B. Stewart 



nerve supply. Patients with this condition cannot control the escape of 
feces which pass through the stricture. Rarely, the perianal tissues become 
honeycombed with abscesses and multiple sinuses opening in the lumen 
and on the perineum. 

About one-third of women with rectal strictures also have rectovaginal 
fistulas. The fistula is almost always in the midline, distal to the stricture, 
and about 3 or 4 cm. above the fourchette. Fistulas usually become smaller 
following chemotherapy, and occasionally they close spontaneously. Sur- 
gical closure seldom succeeds unless the rectal infection is cured first. 

There has been much argument about how the rectum becomes 
infected. Many of the male patients with rectal lymphogranuloma are 
passive homosexuals, and a few women also probably are infected during 
anal coitus. We think, however, that in most cases the infection begins at 
the fourchette or in the lower vagina and spreads along tissue planes of 
the perineal body to invade the rectum where the fascia is thinnest and the 
vagina and rectum are closest to each other. This is the area where proctitis 
usually begins and the level above which strictures form and at which 
rectovaginal fistulas develop (Fig. 9). 

It is difficult to say how prevalent this disease is. Grant and associates^ 
have shown that over 40 per cent of Jamaican working-class people have a 
positive lymphogranuloma venereum complement fixation test, but this 
might be due to exposure to a related but harmless virus, or to subclinical 
lymphogranuloma infection of short duration, or to persistent but latent 
disease. A study among children shows that over 5 per cent develop a 
positive titer about the age of puberty, which may be a result of sexual 




Figure 8. Prolapse in a nul- 
lipara due to severe rectal stric- 
ture. Note fenestration of labia 
minora. The patient also had 
complete destruction of the 
urethra and a rectovaginal fis- 
tula. (D. B. Stewart in: Lym- 
phogranuloma Venereum. Edited 
by M. M. Sigel, Univ. Miami 
Press, 1962.) 



Lesions of Lymphogranuloma Venereum and Granuloma Inguinale 781 




Rectal Stricture 



Recto- 
Vaginal Fistul^ Probable Course of 
Infection from Initial 
Lesion at Fourchette 
Figure 9. Diagram showing the typical relationship of a rectovaginal fistula to a 
rectal stricture. The infection probably reaches the rectovaginal septum from a primary 
lesion at the fourchette. 



contacts. On the other hand, we have had young patients with lympho- 
granuloma who were undoubted virgins (e.g., the patient in Fig. 7) and 
admitted no history of sexual molestation, so the infection is probably not 
always venereal. 



GRANULOMA INGUINALE (DONOVANOSIS) 

This is primarily a disease of the skin and mucous membranes. There 
is no great difference between the sexes in its incidence or in its manifes- 
tations (Table 3). The earliest lesions are slightly raised flat-topped papules 
which subsequently ulcerate. They may appear anywhere on or near the 
external genitalia or in the vagina. The ulcers are usually irregular in shape 
with an uneven edge which may be bordered by papular lesions which have 
not yet broken down, or may be thickened and rolled (Fig. 10). The base 

Table 3. Common Manifestations oj Granuloma Inguinale in Women 



Papules 
Ulcers 



Vulva 

Perineum 

Groins 



Granulomas — Cervix 
Vagina 

Intrapelvic Thickening and Fibrosis 

Rare Extragenital Lesions 



k 



782 D. B. Stewart 



^ 




Figure 10. Untreated don- 
ovanosis (granuloma inguinale) 
of the vulva (see also Plate VI). 
Lesions like this are often mis- 
taken for carcinoma. (Lawson 
and Stewart: Obstetrics and 
Gynaecology in the Tropics. In 
Press.) 



of the ulcer is a dark-red beefy sheet of granulation tissue which sometimes 
shows a cobblestone pattern. This may be covered with slough if there is 
much secondary infection. The vulvar ulcers are often mistaken for car- 
cinoma. Lesions on the cervix or vaginal vault appear as proliferating red 
masses of granulation tissue which may also be mistaken for carcinoma. 
Frequently these vaginal or cervical lesions are associated with a curiously 
uniform, rubbery thickening of the paracervical tissues extending out to 
the side wall of the pelvis, usually on one side only. We have seen such a 
mass gradually become so dense and fibrous that it completely occluded a 
ureter. 

Extragenital lesions are sometimes found — usually in the mouth, nose 
or pharynx — in patients who also have genital lesions. We have seen one 
case of proven donovanosis of the rectum and rectovaginal septum. 

There is seldom much destruction of tissue, as there is in lympho- 
granuloma venereum, but quite massive swelling or ' 'elephantiasis" may 
develop either while the ulcers are still active (Fig. 11), or after they have 
healed (Fig. 12). The cause of this is obscure; the lymphatics are widely 
dilated but they do not seem to be obstructed, since dye injected into the 
tissue rapidly reaches the regional lymph nodes. 

When the ulcers heal they leave a characteristic smooth, pliable, 
depigmented skin surface (Fig. 12). 

The definite diagnosis of granuloma inguinale depends on seeing the 
Donovan bodies in tissue smears stained with Giemsa's solution. Usually 
they are encapsulated and clustered in the cytoplasm of large mononuclear 
cells. Even in an active case they are difficult to find. We have seldom 



Lesions of Lymphogranuloma Venereum and Granuloma Inguinale 783 



Figure 11. Active donovan- 
osis with hypertrophy of the 
labia (see also Plate VI). (D. B. 
Stewart in Lymphogranuloma 
Venereum. Edited by M. M. 
Sigel, Univ. Miami Press, 1962.) 



I 



Figure 12. Hypertrophy of the 
labia which developed after treat- 
ment of donovanosis. Note depig- 
mented scar. (Lawson and Stewart: 
Obstetrics and Gjniaecology in the 
Tropics. In Press.) 




784 D. B. Stewart 

been able to demonstrate them in histological sections, either by hema- 
toxylin and eosin or silver stains. The histological picture of an active 
ulcer of granuloma inguinale is sometimes characteristic enough to warrant 
a provisional diagnosis. Very often in practice the clinical diagnosis is 
confirmed by a therapeutic test; if the ulcers heal rapidly with intensive 
streptomycin treatment they can be assumed to have been due to granu- 
loma inguinale. We usually give 40 gm. of streptomycin over a period of 
20 days. However, tetracycline is a safer drug to use, since the heavy 
dosage of streptomycin may cause vestibular disturbances. 



COMPARATIVE HISTOLOGY 

The appearance of the ulcers and their main histological features are 
shown in Table 4. 

Table 4. Appearance of the Ulcers and Their Main Histologic Features 



LYMPHOGRANULOMA 
VENEREUM 


GRANULOMA INGUINALE 




Ulcers 


Chronic 

Destructive 

Painless 


Rolled edge 
Red base 
Painful 




Histology 


Chronic appearance 
Fibrosis 
Round cells 
Giant cells 


Subacute appearance 

Pseudo-epitheliomatous 
Micro-abscesses 
Dense exudate 


Possibly premalignant 


Probably premalignant 



The most interesting point about the ulcers of lymphogranuloma 
venereum is that even quite recent ones are interpreted by the pathologist 
as showing a very chronic type of inflammatory reaction, with much 
deposition of collagenous scar tissue interspersed with collections of plasma 
cells, lymphocytes and occasional giant cells. This appearance is difficult 
to reconcile with the tissue destruction which these ulcers produce. Possibly 
there is some interference with the local nerve supply, which could account 
for the painlessness of the ulcers and also for a trophic type of tissue 
destruction, though this is pure speculation. 

The ulcers of granuloma inguinale show a more subacute type of 
inflammation. The epithelium at the margin often shows marked acanthosis 
and a pseudo-epitheliomatous appearance. The granulation tissue of the 



PLATE VI 




Fig. 1. Early ulcer of lympho- 
granuloma venereum situated at the 
fourchette. It was painless and was dis- 
covered accidentally. 



Fig. 4. Partial destruction of the 
urethra due to lymphogranuloma vene- 
reum. The site of the external urethral 
meatus is at A, and the opening of the 
remaining upper part of the urethra at B. 
The patient was still continent of urine. 




Fig. 10. Untreated donovanosis 
(granuloma inguinale) of the vulva. 
Lesions like this are often mistaken for 
carcinoma. 



Fig. IL Active donovanosis with 
hypertrophy of the labia. 



Lesions of Lymphogranuloma Venereum and Granuloma Inguinale 785 

base is densely infiltrated with chronic inflammatory cells and scattered 
macrophages. Many small collections of polymorphonuclear leukocytes 
(micro-abscesses) are present. The capillaries are prominent because the 
cells which form their walls are thickened. 

These appearances have been described in more detail and illustrated 
elsewhere.^' ^ 



RELATION TO CARCINOMA 

A relationship between lymphogranuloma venereum and cancer is not 
convincing. We have seen three patients who developed, respectively, 
carcinoma of the urethra, of the rectum and of the anus late in the course 
of this disease, but this might just be coincidental. 

However, we have no doubt that granuloma inguinale is premalignant. 
Carcinoma of the vulva and carcinoma of the penis are both common in 
Jamaica among young people, and a considerable proportion of these 
patients give a history of having had earlier lesions which were charac- 
teristic of granuloma inguinale and which healed with antibiotic treatment 
only to break down again as proven carcinoma. Granuloma inguinale and 
carcinoma have been found together in the same genital lesions in both 
male and female patients (Fig. 13). The association is not unexpected in 
view of the marked epithelial unrest which is characteristic of the margins 



Figure 13. Carcinoma of the 
vulva superimposed on hypertrophy 
due to untreated donovanosis. 




786 D. B. Stewart 

of the ulcers. This is a relationship which merits further research, but 
unfortunately no experimental animal seems to be susceptible to granuloma 
inguinale, and — probably fortunately — the number of human cases of the 
disease seems to be diminishing. Nevertheless it should be investigated as 
a possible addition to our understanding of carcinogenesis. 



REFERENCES 

1. Sigel, M. M. (Ed.): Lymphogranuloma Venereum. University of Miami Press, 1962. 

2. Douglas, C. P.: Lymphogranuloma venereum and granuloma inguinale of the vulva. 

J. Obst. & Gynaec. Brit. Comm. 69 (5): Oct., 1962. 

3. Lawson, J. B. and Stewart, D. B.: Obstetrics and Gynaecology in the Tropics, 

Chapter 25. London, Edward Arnold, in press. 

University of the West Indies 
Mona, Kingston 7 
Jamaica, West Indies 



I 



The Nonvenereal Diseases of the Genitals 

Their Differentiation from Venereal Lesions 

JOHN F. WILSON, M.D., M.S.* 



Syphilis has been designated the great imitator because it can 
mimic so many diseases. It would be impossible even to tabulate a com- 
plete list of such diseases and even more impossible to discuss in detail 
their differential diagnoses. However, a constant awareness of syphilis on 
the part of the physician is of greatest value in coming to an accurate 
diagnosis of the disease. 

It has been aptly stated that in order to know what is 'Venereal" for 
diagnostic purposes, one must first be able to recognize that which is ''not 
venereal." While syphilis may mimic many diseases, careful attention to 
fine details of morphologic change existing on the skin make clinical 
recognition possible and in some instances even essential, as in those cases 
in which laboratory studies are equivocal. 

The anogenital region, because of its location and the changes which 
the skin undergoes in this area, requires special consideration. As most of 
the changes on the cutaneous surface in syphilis tend to be located in the 
genital region, it seems imperative to direct greatest attention to the 
differential diagnosis of those lesions occurring in this area. Also, in view 
of the great increase in homosexual practices in society at the present time, 
especially in larger cities, it seems advisable to include affections of the 
anal region in the differential diagnosis of venereal diseases. 

Moisture and friction produce secondary changes in the anogenital 
areas which tend to obscure the true diagnosis. Intertrigo, folliculitis, 
edema, maceration and even fissuring of the skin produce secondary 
inflammatory changes which, when superimposed upon the original mor- 
phologic picture of disease, tend to make more difficult the accurate 
classification of diseases occurring in this area. Itching when present — and 
it is common because of the inflammation in the area — adds the secondary 
changes of excoriation and lichenification, producing a more confusing 
picture to confound the diagnostician. It is therefore of the greatest impor- 



* Associate Professor of Dermatology and Syphilology, Jefferson Medical College; 
Visiting Lecturer in Dermatology and Syphilology, Graduate School, University 
of Pennsylvania; Chief Dermatologist, Presbyterian and Roxborough Memorial 
Hospitals; Attending Dermatologist, Misericordia Hospital, Philadelphia. 

Supported in part by a grant from the George L. and Emily McMichael Fund for 
Gynecological Research of The Presbyterian Hospital of Philadelphia. 

787 



788 



John F. Wilson 



tance that such secondary changes be treated first by mild soothing 
appHcations so that a diagnosis can then properly be made. 

A listing of the various diseases affecting the anogenital region, 
slightly modified from its original source,* follows: 



I. Pyogenic Diseases 

a. Impetigo 

b. Pyoderma 

c. Ecthyma 

d. Folliculitis 

e. Furunculosis 



f. Carbuncle 

g. Erysipelas 

h. Pyogenic granuloma 

i. Hidradenitis suppurativa 



II. Dermatomycoses 



Superficial 

Tinea cruris 
Erythrasma 
Tinea versicolor 
Favus 
Moniliasis 



b. Deep 

Blastomycosis 
Coccidioidomycosis 
Actinomycosis 
Sporotrichosis 



III. Animal Parasites 

a. Pediculosis pubis 

b. Scabies 



IV. Filterable Viruses 

a. Verruca vulgaris 

b. Condyloma acuminatum 

c. MoUuscum contagiosum 



d. Herpes simplex 

e. Herpes zoster 

f. Vaccinia 



V. Aphthosis, Ectodermosis Erosiva Pluriorificialis and Stevens-Johnson 
Syndrome 

a. Erythema multiforme 

b. Behcet's syndrome 



VI. Neurodermatitis 



VII. 



a. 


Disseminated neurodermatitis 


d. 


Pruritus vulvae 


b. 


Localized neurodermatitis 


e. 


Pruritus of the penis and 


c. 


Pruritus ani 




scrotum 


-,AS 

a. 


SIFIED 

Eczematous dermatitis 


1. 


Pemphigus 


b. 


Intertrigo 


m. 


Hailey-Hailey disease 


c. 


Seborrheic dermatitis 


n. 


Xanthomatosis 


d. 


Sulzberger-Garbe syndrome 


o. 


Scleroderma 


e. 


Acne 


P- 


Cornu cutaneum 


f. 


Edema of the genitals 


q- 


Fox-Fordyce disease 


g- 


Urticaria 


r. 


Lupus erythematosus 


h. 


Psoriasis 


s. 


Hemorrhagic diseases 


i. 


Lichen planus 


t. 


Leukemic diseases 


J- 


Porokeratosis 


u. 


Pseudolues papulosa 


k. 


Lichen nitidus 


V. 


Acanthosis nigricans 



* Callomon, Fritz T. and Wilson, John F.: The Non venereal Diseases of the 
Genitals: Etiology, Differential Diagnosis and Therapy. Springfield, Illinois, Charles C 
Thomas Company, 1956. 



The Nonvenereal Diseases of the Genitals 789 

VIII. Drug Eruptions 

a. Localized 

b. Fixed 

c. Anaphylactic reactions 

IX. Pigmentary Changes 

a. Hyperpigmentation 

b. Depigmentation 

X. Changes of the Pubic and Genital Hair 
XI. Nutritional Deficiencies 

XII. Genital Ulcers 

a. Mechanical, thermal, chemical or physical trauma 

b. Nonvenereal infections 

c. Acute infectious diseases 

XIII. Diffuse Irritative Inflammation of the Glans and Prepuce and of 
the Vulva 

a. Common balanitis and balanoposthitis 

b. Diabetic balanoposthitis and vulvitis 

c. Inflammatory phimosis 

XIV. Progressive Sclerotic Atrophic Processes of the Penis and Vulva 

a. Balanitis xerotica obliterans 

b. Lichen sclerosus et atrophicans 

c. Leukoplakia penis 

d. Leukoplakia vulvae 

XV. Neoplasms 

a. Benign 

b. Malignant 

XVI. Lymphatic System Diseases 

a. The nonvenereal bubo 

b. Elephantiasis lymphangiectatica 

c. Ulcus chronicum vulvae elephantiasticum 

Such a list demonstrates that almost any disease of the integumentary 
system may appear in the genital region and with it occurs all of the 
confusing distortions attendant upon the regional changes of anatomical 
and physical peculiarities in this area. 

No attempt could possibly be made in this short treatise to expound 
in detail upon all of these conditions but a number of them, some common, 
others uncommon, are presented by means of photographs and short case 
histories, to illustrate the difficult problems of the individual case and the 
details of differential diagnosis. As a further aid to diagnosis, 12 of the 20 
black and white photographs are repeated in color. 

2013 Delancey Street 
Philadelphia 3, Pennsylvania 



790 



John F. Wilson 



i 




Figure 1 (see also Plate VII) 



HERPES PROGENITALIS vs. SYPHILITIC CHANCRE 

A white man, aged 49, presents an erosion of the penile meatus of 7 days' 
duration (Fig. 1). It is accompanied by slightly tender left inguinal lymphadeno- 
pathy. There is a history of intercourse with a prostitute about a month ago. There 
is no history of previous lesions in this same area. He occasionally develops herpes 
simplex on the Ups after exposure to sunshine. 

Darkfield examinations on 3 consecutive days were found negative. Serologic 
tests for syphilis were negative. 

The lesion disappeared in about 7 days with the use of an ointment containing 
equal parts of glycerin and a hydrophihc ointment base (carefully avoiding the use 
of an antibiotic which might obscure the diagnosis, if further compUcations arose). 

Note edema and erosion of the meatus. 



The Nonvenereal Diseases of the Genitals 



791 




Figure 2 (see also Plate Vll) 



MULTIPLE HERPES PROGENITALIS vs. MULTIPLE CHANCRES 

A white man, aged 36, shows three superficial eroded lesions of the penis, one 
on the left side of the corona, the other two on the left side of the prepuce (Fig. 2). 
The superior one of the latter forms a ''kissing" contact with the lesion on the 
corona. Duration — 4 days. There is no evidence of regional lymphadenopathy. 
Careful questioning discloses a history of one previous attack in the same area 4 
months ago. No history of suspicious intercourse. 

Smears were negative for Hemophilus ducreyi. The darkfield examinations and 
serologic studies on the blood were found negative. 

The lesions healed uneventfully. The patient has not had another attack in 
the past year. 



792 



John F. Wilson 



w 




Figure 3 



PENILE HERPES ZOSTER vs. SYPHILITIC CHANCRE 

A white man, aged 66, has an ulcerated, black crusted lesion of the right side 
of the penis of 1 week's duration (Fig. 3). There is a red halo of inflammation sur- 
rounding it. The appearance of the ulcer was preceded for 2 days by sharp pain 
radiating over the right flank and extending down the penis. There is tender, right- 
sided inguinal lymphadenopathy. Further examination disclosed an area of crusted, 
ruptured and some unbroken vesicles on the pubic region at the base of the penis 
and extending around the right side of the lower portion of the abdomen from the 
mid-back region. 

Pain was characteristic of herpes zoster in this case but in occasional instances 
it may not occur until several days after the eruption appears or it may even be 
shght or absent. 

This is an example of the importance of examining the entire surface of the skin. 



PLATE VII 





Fig. 1. Herpes progenitalis vs. syphi- Fig. 2. Multiple herpes progenitalis 

litic chancre. vs. multiple chancres. 





Fig. 6. Acute simple balanitis vs. 
syphilitic chancre. 



Fig. 7. Psoriasis vs. secondary syph- 
ilis. 





Fig. 8. Erythema multiforme vs. Fig. 10. Pyoderma vs. early syphilis, 

syphilitic chancre. 

Note: See text for Case Histories. 



The Nonvenereal Diseases of the Genitals 



793 




Figure 4 



MONILIASIS WITH ULCERATION AND ACUTE EROSIVE BALANITIS vs. 

SYPHILITIC CHANCRE 

A white man, aged, 48, has a crusted ulcer of the shaft of the penis and redness, 
oozing and edema of the prepuce and corona of 2 weeks' duration (Fig. 4). The 
ulcer is soft and superficial, the balanitis is acute and oozing with involvement of 
the entire prepuce adjacent to the corona. 

Darkfield examination was negative on 3 successive days. Serologic tests for 
syphihs were negative. Smears for Hemophilus ducreyi were negative. Candida 
albicans was cultured from both areas on Pagano medium. 

Both lesions healed in about a week with a simple drying lotion. 



794 



John F. Wilson 




BALANOPOSTHITIS IN A DIABETIC vs. PHIMOTIC CHANCRE 
OF REDUNDANT PREPUCE 

A white man, aged 58, has burning, redness and sweUing of the distal portion 
of the penis of 3 weeks' duration (Fig. 5). He is an alcohoHc who is also a diabetic, 
is obese and negligent with his diet. Retraction of the prepuce disclosed no evidence 
of chancre or other ulceration or erosion of the surface. Complete visuahzation by 
retraction is essential for accurate diagnosis. 

The patient responded to treatment with simple drying lotions and improve- 
ment of his diabetes. 



The Nonvenereal Diseases of the Genitals 



795 




Figure 6 (see also Plate VII) 



ACUTE SIMPLE BALANITIS vs. SYPHILITIC CHANCRE 

This lesion (Fig. 6) occurred in a white man, aged 49, following extramarital 
exposure. These are superficial erosions without infiltration and are multiple rather 
than single. They have appeared 2 days after extramarital intercourse. There is 
tenderness of the entire area. The regional lymph nodes are not affected. It was 
felt that the diagnosis of syphihs could be excluded on the chnical findings but in 
view of the questionable exposure, the patient was kept under surveilance and the 
diagnosis of syphilis was later excluded. 



796 



John F. Wilson 




Figure 7 (see also Plate VII) 



PSORIASIS vs. SECONDARY SYPHILIS 

The patient, aged 54, has had a papulosquamous eruption of the glans penis 
especially at the corona for the past several weeks (Fig. 7.) The scales on the 
surface are grayish, there is very Httle inflammatory reaction. The patient has a 
history of an eruption of the elbows and knees of 5 years' duration, readily recog- 
nized as psoriasis vulgaris. It is felt that the lack of erosion and infiltration, plus 
the rather typical fine mica-like scale and the evidence of pin-point bleeding, 
characteristic of psoriasis, were sufficient to exclude syphilis. 

The location of the lesions in these areas points to the importance of Kobner's 
phenomenon (friction and pressure in psoriasis) in coitus. 



The Nonvenereal Diseases of the Genitals 



797 




Figure 8 (see also Plate VII) 



ERYTHEMA MULTIFORME vs. SYPHILITIC CHANCRE 

A white man, aged 35, developed this superficially eroded penile lesion affecting 
the glans 4 days ago (Fig. 8). There is a similar eroded lesion of the lower Hp at the 
center. Careful examination of the hands and wrists shows the beginning appear- 
ance of "iris" lesions of erythema multiforme. Further observations showed the 
classic picture of erythema multiforme. 

Always examine the entire skin surface. 



798 



John F. Wilson 




Figure 9 



PYOGENIC GRANULOMA vs. SYPHILITIC CONDYLOMA 

A white man, aged 56, has had a *'wart" of the area of the penile meatus which 
has gradually enlarged in size during the past year (Fig. 9). It is dry and shows no 
evidence of inflammatory reaction. It is not painful and the regional lymph nodes, 
while shotty, are not enlarged. 

The lesion was excised and showed pyogenic granuloma. Microscopic exami- 
nation of the tissue is essential for the recognition of tumorous lesions. It could 
have been a cancerous lesion as well. 



The Nonvenereal Diseases of the Genitals 



799 




Figure 10 (See also Plate VII) 



PYODERMA vs. EARLY SYPHILIS 

A Negro woman, aged 27, was found to have eroded papules on the right labia 
majora at 10 to 11 o'clock in the above figure. Darkfield examination and serologic 
tests for syphilis were found to be negative. The surfaces of the lesions were eroded. 
There was a grayish, thin membrane and the lesions were not infiltrated. Beta 
hemolytic streptococci were isolated from the lesions. They disappeared in a few 
days with treatment, using a topical antibiotic (neomycin) ointment. 



800 



John F. Wilson 





Figure 11 



PEDICULOSIS PUBIS 

While not truly venereal in origin, the nits and lice of pediculosis pubis are not 
infrequently found to be spread during intercourse. This case (Fig. 11) occurred 
in a white man, aged 59, who had severe itching with an eczematous eruption of 
his lower abdomen and upper, inner thighs for the past 7 days, following several 
days after intercourse with a prostitute. Antiparasitic medications produced 
prompt rehef. 

In this instance this was proved to be the only disease contracted by the 
patient. 

Note the tiny nits on the hair shafts and also the larger dark areas of pediculi 
on the skin, under the hair. 



PLATE VIII 



Fig. 12. Squamous cell epithelioma 
of vulva vs. condyloma latum. 



Fig. 15. Molluscum contagiosum, 
anal vs. condylomata lata. 




Fig. 17. Leukoijlakia vs. mucous 
patches. 




Fig. 19. Lichen sclerosus et atrophi- 
cans vs. mucous patches. 




Fig. 18. Localized neurodermatitis 
vs. leukoplakia vs. mucous patches. 




Fig. 20. Acute vulvitis (Trichomonas 
vaginalis vs. gonorrhea). 



Note: See text for Case Histories. 



The Nonvenereal Diseases of the Genitals 



801 




Figure 12 vsee alt^o i'iate VIII) 



SQUAMOUS CELL EPITHELIOMA OF VULVA vs. CONDYLOMA LATUM 

Such a far advanced lesion as demonstrated above with firm consistency and 
ulceration at the surface, came as a result of the epithelioma. A long history of 
gradual enlargement in size during the last year left little doubt of the diagnosis of 
carcinoma. Microscopic examinations of this tissue disclosed it to be of Grade 3 
type. 

Bilateral firm painless inguinal lymphadenopathy is a result of regional 
metastasis. This is an example of the problem of delayed diagnosis in the manage- 
ment of cancer in this area. It is a common problem and histories of 1 and 2 years' 
duration are not unusual. 



802 



John F. Wilson 






Figure 13 



CICATRICIAL SUPERFICIAL BASAL CELL EPITHELIOMA vs. TERTIARY 

SYPHILIS, GUMMA 

A white woman, aged 71, presents an ulcerated, crusted and scarred lesion of 
the pubic region of 4 years' duration (Fig. 13). There is a marginated, rolled 
serpiginous border and areas of ulceration spread throughout. Microscopic examina- 
tion clarified the diagnosis of basal cell epithelioma. Serologic tests for syphilis 
were negative. 



The Nonvenereal Diseases of the Genitals 



803 




SQUAMOUS CELL CARCINOMA OF PERIANAL REGION vs. 
SYPHILITIC CHANCRE 

A white woman, aged 43, has had a tender lump of the anal ring for the past 
month (Fig. 14). There is exquisite tenderness on cleansing after a bowel movement. 
Microscopic examination of the lesion shows a squamous cell epithelioma, Grade III. 
Serologic tests for syphiUs are negative. Darkfield studies were not done because of 
the probabihty of cancer. 



,i 



804 John F. Wilson 



"W^" '*■ 'fs^ 



^^ 




Figure 15 (see also Plate VIII) 



MOLLUSCUM CONTAGIOSUM, ANAL vs. CONDYLOMATA LATA 

A white male student, aged 23, noticed tiny lumps at the anal region (Fig. 15) 
when cleansing the area after a bowel movement. His roommate was found to have 
similar lesions on the penis. Scrapings from these lesions and the penile lesions of 
the roommate showed the classical bodies of moUuscum contagiosum. This is not 
ordinarily considered to be a venereal disease. The students are homosexuals. Both 
were found to have negative serologic tests for sypliilis. 



The Nonvenereal Diseases of the Genitals 



805 





Figure 16 



HIDRADENITIS SUPPURATIVA, PERIANAL vs. SYPHILITIC CHANCRE 

A white woman, aged 43, developed tender raised tumors in the perianal and 
vulvar regions (Fig. 15). They have appeared at varying intervals for the past 6 
months. When they rupture or are incised, a small amount of thick, creamy, 
yellowish pus exudes from them. They then usually heal gradually but occasionally 
drain for several months. 

Cultures showed Staphylococcus aureus. 



t 



806 



John F. Wilson 




Figure 17 (see also Plate VIII) 



LEUKOPLAKIA vs. MUCOUS PATCHES 

A white woman, aged 53, has had itching of the vulva for the past 20 years. 
Three years ago she consulted a gynecologist for treatment of the itching. Examina- 
tion showed thickened, whitish patches of the vulva (Fig. 17). These have gradually 
increased in size. Several biopsies have shown hypertrophic changes in the tissue 
but no evidence of carcinomatous change. Occasional fissures develop and are 
painful. 

Treatment with the use of creams containing topical steroids gave only slight 
relief of itching and only sHght evidence of improvement. 

Vulvectomy was performed and all of the diseased tissue removed. 



The Nonvenereal Diseases of the Genitals 



807 




Figure 18 (see also Plate VIII) 



LOCALIZED NEURODERMATITIS vs. LEUKPOLAKIA vs. MUCOUS PATCHES 

A white woman, aged 58, had consulted a physician for treatment of an itching 
condition of the vulva. White patches were seen and were concluded to be leuko- 
plakia. Vulvectomy was performed and the itching improved for several months. 
It then recurred and with it white patches appeared again in the scars of the opera- 
tive site (Fig. 18). 

The itching and the whitish patches disappeared with several weeks treatment 
using a topical steroid cream. It is concluded that the final diagnosis is localized 
neurodermatitis. 



808 



John F. Wilson 




Figure 19 (see also Plate VIII) 



LICHEN SCLEROSUS ET ATROPHICANS vs. MUCOUS PATCHES 

A white woman, aged 46, has had itching of the vulvar region for the past 
6 months. Examination of the vulva showed almost a complete disappearance of 
the labia minora and the labia majora were less noticeable. There is a whitish 
appearance of the entire vulvar area extending down and across the perineum to 
the perianal region producing a sort of "hour-glass" appearance. 

At the right posterior portion of the inner surface of the labia minora there 
are hemorrhagic patches and the mucous membrane of the entire vestibule has a 
glazed, thin appearance. 

Further examination of the general surface of the skin shows white delled 
papules of Hchen sclerosus et atrophicans of the sides of the neck, presternal region 
and the inguinal folds. Some of these papules in the right inguinal folds can be seen 
in the above illustration. 



The Nonvenereal Diseases of the Genitals 



809 




Figure 20 Acute vulvitis (see also Plate VIII) 



t 



TRICHOMONAS VAGINALIS vs. GONORRHEA 

A white housewife, aged 32, complains of itching and burning of the vulva of 
2 weeks' duration. There is a profuse thick yellowish white discharge from the 
vagina which has been present for several months but it has been increasingly 
severe for the past month. There is bilateral tender inguinal lymphadenopathy. 

Note above the edema of the labia minora and the vesiculation of the inner 
surface of the right labia majora. 

Studies for the gonococcus in smears and culture were negative. Numerous 
Trichomonas organisms were found. 

The eruption of the vulva healed when the discharge disappeared after treat- 
ment of the Trichomonas infection. 



Appendix 



SUMMARY OF THE TREATMENT OF SYPHILIS 
With Notes on Prognosis and Follow-up 

Primary, Secondary and Early Latent Syphilis 

Benzathine Penicillin G — 2.4 million units total (1.2 million units in each buttock) 
by intramuscular injection. 

or: PAM (Procaine Penicillin G with 2 per cent aluminum monostearate) — 
4.8 million units total usually given 2.4 million units at first session, as above, 
and 1.2 million units at each of two subsequent injections 3 days apart. 

or: Aqueous Procaine Penicillin G — 600,000 units daily for 8 days to total 4.8 
million units. 

or: Alternate antibiotics. (See Antibiotics.) 

Prognosis : Primary. Lesions heal rapidly. Serologic titer falls rapidly to nonreactive. 
Secondary. Lesions heal rapidly. Serologic titer reverts steadily to non- 
reactive, although not as rapidly as in primary syphihs. 
Early Latent. (See Latent Syphihs.) 

Follow-up: Clinical inspection and quantitative STS monthly for 6 months, then 
at 3-month intervals for 1 year. If only one spinal fluid examination is to be 
done, the preferred time is 12 months' post- treatment. 

Note: Report morbidity by stage to Department of Public Health. Very important this 
patient be interviewed for contacts. Request epidemiologic assistance from local or 
State health department. 



Latent Syphilis 

Benzathine Penicillin G. If no spinal fluid examination is done, treatment must 
encompass the possibihty of asymptomatic neurosyphihs. (See Late Syphihs.) 
With nonreactive spinal fluid examination, 2.4 million units (1.2 in each 
buttock at a single session). 

or: PAM — 4.8 milhon units total usually given 2.4 miUion units at first session, 
and 1.2 milhon units at each of two subsequent injections 3 days apart. 

or: Aqueous Penicillin G — 4.8 miUion units total given 600,000 units daily for 
8 days. 

* Adapted from Syphilis — Modern Diagnosis and Management. U. S. Department 
of Health, Education and Welfare, Public Health Service, Publication No. 743, U. S. 
Government Printing Office, Washington, D. C. 

811 



812 Appendix 

or: Alternate antibiotics. 

Prognosis: Serologic titer will remain stable or decline gradually, but may remain 
permanently reactive. 

Follow-up: Early Latent. Same as for primary syphilis. 

Late Latent. Quantitative STS at 6-month intervals for 2 years. Either a 
static or a falling titer may be considered satisfactory. Persistence of reactive 
STS alone must not be considered as an indication for retreatment. At least one 
nonreactive spinal fluid examination, either at diagnosis or before discharge. 

Syphilis in Pregnancy 

Treatment dependent on stage. No additional medication is necessitated by 
pregnancy. 

Prognosis : Dependent on stage. 

Follow-up; Quantitative STS in each trimester; monthly for last 3 months. 



Congenital Syphilis 

Early 

Under 2 years* duration, total dose of 100,000 units of PAM or aqueous penicillin 
per kilogram of body weight. May be given in divided doses at 2 or 3 day 
intervals. 

or: 50,000 units of Benzathine peniciUin G per kilogram of body weight total dose 
administered as a single intramuscular injection. 

Prognosis: Lesions heal rapidly. Serologic titer descends rapidly to nonreactive. 

Follow-up : Same as primary syphilis. 

Late 

If spinal fluid is nonreactive, treat as late latent syphilis. If spinal fluid is reactive, 
treat as neurosyphihs. 

Note: In treating late congenital syphilis in patients under 12 years of age, dosage of 
penicillin should he adjusted for age and weight. 

Note: Interstitial keratitis usually will not respond to penicillin therapy alone. In addi- 
tion to penicillin, corticosteroids {such as hydrocortisone) may be used locally in 
the eyes, usually with good response. Advice of an ophthalmologist should be 
sought. 

Note: Management of late complications of congenital syphilis often requires indi- 
vidualized, specialized care. 

Prognosis: Serologic titer may be expected to remain the same or to descend 
slowly. Active lesions will heal, and further damage will not occur. In spinal 
fluid, cell count and total protein will return to normal, but titer may remain 
static or descend slowly. 

Follow-up: If spinal fluid examination is nonreactive, quantitative serology at 
6-month intervals for 2 years. If spinal was not performed initially, it should 
be done before patient is discharged. 



Appendix 813 

If spinal fluid is reactive, quantitative serology and spinal fluid examination 
at 3-month intervals for first year, and at 6-month intervals for the second year. 
When cell count and total protein return to normal, the disease no longer is 
active in the spinal fluid. The spinal fluid may remain reactive for years simi- 
larly to the blood serum. 



Late Syphilis (Asymptomatic and Symptomatic Neurosyphilis; 
Cardiovascular* and Late Benign Syphilis) 

Benzathine Penicillin G — 6.0 to 9.0 miUion units total, given 3.0 million units at 
7-day intervals. (Any benefit from more than 10 million units is doubtful and 
has not been demonstrated.) 

or: PAM — 6.0 to 9.0 milHon units total, given L2 million units at 3-day intervals. 
Any benefit from more than 10 million units is doubtful and has not been 
demonstrated. 

or: Aqueous Procaine Penicillin G — 6.0 to 9.0 million units total, given 600,000 
units daily. Any benefit from more than 10 million units is doubtful and has 
not been demonstrated. 

Prognosis: Asymptomatic Neurosyphilis. Both blood and spinal titers will remain 
relatively stable or will decHne slowly. Cell count will return to normal in 
spinal fluid within 6 months. Total protein will return to normal level in 6 
months to 1 year. 

Symptomatic Neurosyphilis. Blood and spinal fluid titers will remain stable 
or descend slowly. Cell count and total protein will return to normal. Destruc- 
tion will be halted. Patient may show some recovery of impaired faculties as 
heahng takes place. Where organic damage of the nervous system has pro- 
gressed to destruction of nerve cells, recovery of function will not occur. 

Late Benign and Cardiovascular Syphilis. Late benign lesions heal dramati- 
cally. In cardiovascular syphiHs, damaged or scarred vessels and valves will 
not be restored to normal function. 

Follow-up: Neurosyphilis. Quantitative serology and spinal fluid examination at 3- 
month intervals for the first year, and at 6-month intervals for second year. 
When cell count and total protein return to normal, the disease no longer is 
active in the spinal fluid. The spinal fluid may remain reactive for years 
similarly to the blood serum. 

Late Benign and Cardiovascular Syphilis. Same as late latent syphilis. 



Oral Medication 

Oral medication is not the preferred treatment in syphilis since absorption is 
highly variable and patient cooperation in taking all the treatment is not always 
obtained. 

*Note: The administration of penicillin to a person with decompensation due to 
cardiovascular syphilis is not an emergency, and the demand is to treat the heart first 
and the syphilis second. The decompensated patient should be given cardiotonic drugs 
and diuretics first; then, penicillin may be started in full doses without preliminary heavy 
metal treatment. If the patient is well compensated, penicillin treatment may be begun 
immediately since there appears to be no demonstrable risk from penicillin alone in 
these cases. 



814 Appendix 

Alternate Antibiotics 

When penicillin sensitivity precludes use of this drug of choice, erythromycin 
and tetracychne are the best alternate drugs. Recommended dosage is 20 to 30 gm. 
of erythromycin and 30 to 40 gm. of tetracychne given over a period of 10 to 
15 days. 

Treatment with such alternate antibiotics must be accompanied by close 
follow-up of the syphihtic patient since none af these drugs has had adequate 
evaluation in all stages of syphihs. Spinal fluid examinations must be done as part 
ot follow-up after this type of therapy. 



Cumulative Index 



Note: Page numbers of symposium and article titles are 
in boldface type. 



Abscess of liver, amebic, Jan., 166, 172 

Absorptive disorders. See Malabsorption. 

Acetophenazine dimaleate, March, 465 

Addiction, narcotic, diagnosis, use of an- 
tagonists for, March, 436 

Adenoma of gallbladder, Jan., 10 

Adenomyomatosis of gallbladder, pathol- 
ogy, roentgen diagnosis, etiology and 
significance, Jan., 9-36 

Adrenal failure, acute, shock in, treatment, 
March, 325 

Adrenalin. See Epinephrine. 

Albamycin, March, 272 

Albumin, CR^^-labeled, for testing absorp- 
tion, Jan., 132 
metabolism, in protein-losing enterop- 
athy, Jan., 88 

Aldolase, serum, in liver disease, Jan., 201 

Aldomet, March, 330, 335 

Alpha-methyldopa, in hypertension, 
March, 330, 335-345 
side effects and toxicity, March, 341 

Alseroxylon, March, 468 

Amebiasis, diagnosis and management, 
Jan., 159-175 

American Medical Association, role of, in 
syphilis, May, 583-586 

Amines for protection against radiation, 
March, 554 

1-Aminocyclopentanecarboxylic acid, 

March, 516 

Aminopeptidase, leucine, serum, in liver 
disease, Jan., 203 
in pancreatic disease, Jan., 207 

Aminothiols for protection against radia- 
tion, March, 549 

Amitriptyline, March, 496 

Ammonium chloride for urinary acidifica- 
tion, March, 297 

Amphetamines as antidepressants, March, 
488 

Amphotericin B, March, 276 

Ampicillin, March, 262 

Amylase, serum, in pancreatic disease, 
Jan., 204 

Analexin, March, 449 

Analgesics in headache, March, 447 

Ancillin, March, 261 

Androgens in carcinoma of breast, March, 
514 

Anemia, pernicious, deficiency factors, 
Jan., 180 



Anemia (Continued) 

pernicious, differential diagnosis, Jan., 
183 
neurologic manifestations, Jan., 177- 
186 
Anesthesia, use of antagonists, March, 434 
Aneurysm, aorta, abdominal, gastroin- 
testinal symptoms, Jan., 141 
syphilitic. May, 691-696 
Angina, abdominal, Jan., 141 
pectoris, anticoagulants in, long-term, 
March, 364 
Angiotensin 11 in shock, March, 314, 315 
Anisotropine methylbromide, March, 404 
Anovlar, March, 531, 540 
Ansolysen, March, 314 
Antazoline in arrhythmias, March, 372 
Antibiotics, in amebiasis, Jan., 170 
in cancer, March, 511 
in gonorrhea, May, 750, 762, 769 
in syphilis. May, 634, 635, 718, 811-814 
in urologic infections, March, 302 
newer, March, 255-292 
Anticancer agents, newer, March, 501-527 
Anticholinergics, modern, evolution of, 
March, 399 
newer, March, 399-409 
structural formulas, March, 401 
Anticoagulants, dosages, March, 358 
hemorrhagic complications, March, 366 
in coronary artery disease, current 

myths and realities, March, 355-370 
in myocardial infarction, March, 358, 

363, 365 
long-term, in angina pectoris, March, 
364 
in chronic coronary artery disease, 
March, 363 
Antidepressant drugs, March, 483-500 
Antihypertensive drugs, March, 329-333 
Antimicrobial drugs, newer, March, 255- 

292 
Antiovulatory drugs, March, 529-545 
Antipruritics, oral, newer developments in, 

March, 411-419 
Antistine, March, 372 
Aorta, aneurysm, abdominal, gastroin- 
testinal symptoms, Jan., 141 
syphilitic. May, 691-696 
insufficiency, syphilitic. May, 689 
Aortitis, syphilitic. May, 685 
Aramine, March, 314, 316 

815 



816 



Cumulative Index 



Arfonad, March, 314 

Arlidin, March, 314 

Arrhythmias, cardiac, electrical depolari- 
zation of heart in, March, 382 
treatment, March, 318 

newer agents in, March, 371-387 

Arthritis in congenital syphihs, May, 712 

Ascites in heart disease, Jan., 139 

Aspartic acid, March, 498 

Atarax, March, 475 

Atherosclerosis, hypercholesterolemia in, 
treatment, March, 347-354 

Azacyclonol, March, 476 

Azauridine in cancer, March, 508 



Bacitracin, newer data on, March, 285 
Balanitis, acute, vs. chancre, May, 795 
Balanoposthitis, diabetic, vs. chancre. 

May, 794 
Benactyzine, March, 476, 494 
Betamethasone in pruritus, March, 418 
Biliary disease, obstructive, oral anti- 
pruritic therapy in, March, 418 
Biopsy, in carcinoma of colon, Jan., 216 
in protein-losing enteropathy, Jan., 83 
liver, in differentiation of primary 
hepatic and posthepatic cholestasis, 
Jan., 60 
peroral, in malabsorptive disorders, 
Jan., 132 
Bishydroxycoumarin, March, 357, 358 
Boeck-Bruusgaard investigation of natural 
course of untreated syphilis, re-study of. 
May, 613-623 
Bone(s), syphilis of. May, 673-678 

prenatal, May, 710 
Breast, carcinoma, steroid therapy, March, 

513 
Buboes in lymphogranuloma inguinale. 

May, 774 
Buclizine, March, 475 
Busulfan in cancer, March, 508. 
Butigetic in headache, March, 447 



Cachexia in heart disease, Jan., 139 

Can til, March, 405 

Carbohydrate absorption, measuring, Jan., 

127 
Carcinoma, chemotherapy, drug sensi- 
tivity tests, March, 517 
mechanism of action, March, 501 
newer agents in, March, 501-527 
gastrointestinal, serum enzymes in, Jan., 

209 
immunochemical therapy, March, 519 
perianal, vs. chancre. May, 803 
of colon, management, contribution of 
internist, surgeon and radiotherapist, 
Jan., 215-226 
physical agents used against, March, 520 
Cardiovascular disease, gastrointestinal 

manifestations, Jan., 137-142 
Cardiovascular syphilis, May, 685-696 
treatment. May, 813 



Carisoprodol in headache, March, 448 
Carotene, serum, in malabsorption, Jan., 

121 ; 

Carphenazine maleate, March, 465 * 

Catecholamines in shock, March, 313 
Cathomycin, March, 272 
Celestone, March, 418 
Celiac disease, diagnosis, laboratory pro- 
cedures in, Jan., 117-136 
Cephalosporin in urologic infections, 

March, 302 
Cephalothin, March, 280 
Chancre, May, 627, 628 

vs. acute simple balanitis. May, 795 

vs. diabetic balanoposthitis. May, 794 

vs. erythema multiforme. May, 797 

vs. herpes progenitalis, May, 790, 791 

vs. penile herpes zoster. May, 792 

vs. penile moniliasis. May, 793 

vs. perianal carcinoma. May, 803 

vs. perianal hidradenitis suppurativa. 
May, 805 
Chemotherapy, adjuvant, in carcinoma of 
colon, Jan., 220 

of carcinoma, newer agents in, March, 
501-527 
Chlorambucil in cancer, March, 508 
Chloramphenicol, in gonorrhea. May, 762, 
769 

newer data on, March, 286 
Chlordiazepoxide, March, 472 

in headache, March, 449 
Chlormadinone, March, 532 
Chlormerodrin in urologic infections, 

March, 298 j 

Chlormezanone, March, 472 | 

Chloromycetin. See Chloramphenicol. \ 

Chlorpromazine, cholestasis due to, Jan., l 

55, 57 i 

Chlorprothixene, March, 464, 467 | 

Chlorthalidone in hypertension, March, | 

330 ! 

Cholecystitis cystica, Jan., 10 

glandularis proliferans, Jan., 10 
Cholecystoses, hyperplastic, Jan., 23 
Cholestasis, due to drugs, Jan., 55, 57 

intrahepatic, vs. posthepatic jaundice, 
methods of diagnosis, Jan., 53-65 

of primary hepatic diseases, Jan., 53 
Cholesterol, blood, efficacy of drugs in 

lowering, March, 347-354 
Cholestyramine in pruritus of obstructive 

biliary disease, March, 418 
Cholinesterase, serum, in liver disease, 

Jan., 203 
Choloxin, March, 349 
Chorioretinitis, syphilitic, May, 682 
Choroiditis, syphilitic. May, 714 
Citric acid cycle, enzymes, serum, in liver 

disease, Jan., 202 
Cloxacillin, March, 260 
Cluster interviewing in syphilis. May, 

650 
Clutton's joints in prenatal syphilis, May, 

712, 713 
Colistimethate, March, 272 
Colistin methanesulfonate, March, 272 



Cumulative Index 



817 



Colitis, ulcerative, irreversibility and re- 
versibility of, Jan., 143-157 
Colon, carcinoma, diagnosis, Jan., 216 
incurable, palliation in, Jan., 221 
management, contribution of intern- 
ist, surgeon and radiotherapist, 
Jan., 215-226 
pain in, treatment, Jan., 224 
surgery in, preparation, adjuvants and 
follow-up, Jan., 218 
Coly-Mycin, March, 273 
Coma, hepatic, management, Jan., 37-51 
Common duct, disease, serum enzymes in, 

Jan., 204 
Condyloma latum. May, 630 

vs. anal moUuscum contagiosum, May, 
804 
vs. epithelioma of vulva, May, 801 
vs. pyogenic granuloma. May, 798 
Contact interviewing in syphilis, May, 649 
Contact investigation, importance of, in 

control of syphilis. May, 637-651 
Contraceptive drugs, March, 529-545 

side effects, March, 539 
Coronary artery disease, anticoagulant 
therapy, current mvths and realities in, 
March, 355-370 
Coronary ostia, stenosis, syphilitic, May, 

691 
Corticosteroids, in carcinoma of breast, 
March, 515 
in pruritus, March, 418 
Cortisone in headache due to cranial 

arteritis, March, 454 
Cotazym, March, 395 
Coumadin, March, 357, 358 
Coumarin, dosages, March, 357, 358 
Cranberry juice for urinary acidification, 

March, 296 
Cyanide for protection against radiation, 

March, 555 
Cyclamycin, March, 271 
Cyclophosphamide in cancer, March, 509 
Cycloserine, March, 275 

in urologic infections, March, 302 
Cyproheptadine in pruritus, March, 416 
Cystadenoma of gallbladder, Jan., 10 
Cysteamine for protection against radia- 
tion, March, 550 
Cysteine for protection against radiation, 

March, 550 
Cytology, exfoliative, in carcinoma of 
colon, Jan., 216 
in gastric ulcer, Jan., 110 
Cytoxan, March, 509 



Danilone, March, 358 

Darbid, March, 402 

Darcil, March, 256 

Daricon, March, 403 

Darvon, March, 448 

Deafness, neural, in prenatal syphilis, 

May, 712 
Deanol, March, 498 
Declinax, March, 331 



Declomycin, March, 269 

Dehydrogenases, serum, in liver disease, 
Jan., 201, 202 

Demethylchlortetracycline, March, 269 

Deoxyribonuclease in pancreatic disease, 
Jan., 207 

Depolarization, electrical, of heart in 
arrh.ythmias, March, 382 

Depression, drug therapy, March, 483-500 
syndromes, classification, March, 484 

Descrpidine, March, 469 

Desipramine, March, 497 

Dexbrompheniramine in pruritus, March, 
414 

Dexbrompheniramine-fluphenazine in pru- 
ritus, March, 417 

Dexchlorpheniramine in pruritus, March, 
414 

Diabetes mellitus, pancreatitis with, 
chronic, Jan., 237 

Diazoxide in hypertension, March, 331 

Dibenzyline, March, 314 
in shock, March, 314 

Dicumarol, March, 357, 358 

Diet in hypercholesterolemia, March, 350 

Digestive tract, diseases, symposium on, 
Jan., 1-248 

Digitalis in arrhythmias, new light on, 
March, 378 

Dihvdrostreptomycin, newer data on, 
March, 284 

Dilantin in arrhythmias, March, 376 

Dimethindene in pruritus, March, 415 

Dimocillin, March, 257 

Diperm, March, 417 

Diphenicillin, March, 261 

Diphenylhydantoin in arrhythmias, 
March, 376 

Disomer, March, 414 

Divert iculosis, intramural, of gallbladder, 
Jan., 10 

Dolonil in urologic infections, March, 294 

Donovanosis, gvnecologic lesions. May, 
773-786 

Dropsprin, March, 448 

Drugs, anticancer, newer, March, 501-527 
anticholinergic, newer, March, 399-409 
antidepressant, March, 483-500 
antihypertensive, newer, March, 329- 

333 
antimicrobial, newer, in urological infec- 
tions, March, 293-304 
antipruritic, oral, March, 611-619 
cholestasis due to, Jan., 55 
contraceptive, March, 529-545 
new, eflficacy of, March, 253-561 
tranquilizing, newer, March, 459-481 

Duodenum, ulcer, complications, manage- 
ment of, Jan., 93-102 

Duphaston, March, 533 

Dysentery, amebic, acute, treatment, 
Jan., 171 



EcTYLUREA, March, 477 
Elavil, March, 496 



818 



Cumulative Index 



Electrolytes in intestinal obstruction, /an., 

72 
Embolism, pulmonary, treatment, March, 

317 
Emylcamate, March, 472 
Endocrine therapy in carcinoma of breast, 

March, 513 
Endometrium, carcinoma, endocrine ther- 
apy, March, 516 
Enovid for contraception, March, 531, 540 
Ensidon, March, 496 
Enteropathy, protein-losing, Jan., 75-91 
case presentation and development, 

Jan., 77 
diagnosis, Jan., 79-84 
pathophysiology, Jan., 87 
therapeutic approach, Jan., 85 
Enzymes, serum, in diseases of gallbladder 
and common duct, Jan., 204 
in gastrointestinal diseases, Jan., 189- 

214 
in liver disease, Jan., 196, 200 
in pancreatic disease, Jan., 204 
patterns of abnormality, Jan., 210 
Epidemiologic methods in syphilis, im- 
portance of, in control, May, 639 
private patients lost to. May, 575 
Epinephrine in shock, March, 314 
Epithelioma, of vulva, vs. condyloma 
latum. May, 801 
pubic, vs. gumma, May, 802 
Equanil, March, 474 
Erythema multiforme, penile, vs. chancre. 

May, 797 
Erythromycin in syphilis. May, 635, 814 
Erythromycin estolate, March, 270 
Erythromycin propionate, March, 270 
Esophagus, perforation, spontaneous, 

Jan., 3-8 
Estrogens, in carcinoma of breast, March, 
515 
in hypercholesterolemia, March, 349 
Ethoheptazine citrate in headache, March, 

448 
Ethynylestrenol for contraception, March, 

532 
Eutonyl, March, 492 
Eyes, syphilis of. May, 682 



Facies, syphilitic, May, 714, 715 

Fat, absorption, indirect indices, Jan., 121 
fecal, chemical analysis, Jan., 120 
isotopically labeled, in diagnosis of 
steatorrhea, Jan., 123 

Feces. See Stools. 

Fetus, hypoxia in, narcotic-induced, treat- 
ment, March, 433 

Fibromyoadenoma of gallbladder, Jan., 10 

Fluids, administration, in intestinal ob- 
struction, Jan., 72 

5-Fluoro-2'-deoxyuridine in cancer, March, 
507 

5-Fluorouracil, in cancer, March, 506 

Forhistal, March, 415 

Fournier, Jean- Alfred, May, 597 



Freezing, gastric, in peptic ulcer, Jan., 101 

Frenquel, March, 476 

Frontal bosses, syphilitic. May, 714 

Fucidin, March, 283 

Fungizone, March, 276 

Furadantin, newer data on, March, 287 



Gallbladder, adenomyomatosis, pathol- 
ogy, roentgen diagnosis, etiology and 
significance, Jan., 9-36 

disease, serum enzymes in, Jan., 204 

Rokitansky-Aschoff sinuses, Jan., 10, 11 
Garymycin, March, 281 
Gastrectomy, syndrome following, Jan., 

182 
Gastric. See Stomach. 
Gastroenterology, symposium on, Jan., 1- 

248 
Gastroenteropathy, protein-losing, Jan., 

75-91 
Gastrointestinal diseases, serum enzymes 
in, Jan., 189-214 
symposium on, Jan., 1-248 
Gastrointestinal manifestations of cardio- 
vascular disease, Jan., 137-142 
Gastrointestinal syphilis. May, 681 
Gastroscopy in gastric ulcer, Jan., 110 
Genitals, nonvenereal diseases and their 

differentiation from venereal diseases. 

May, 787-813 
Gentamycin, March, 281 
Globulin, immune, in measles, March, 306 
Glucose tolerance test in malabsorption, 

Jan., 127 
Glycopyrrolate, March, 402 
Gonorrhea, May, 767-772 

clinical course, May, 768 

diagnostic advances, May, 760 

incidence, May, 767 

present knowledge, research and control 
efforts. May, 755-765 

treatment. May, 757, 769 
failure. May, 757 

vs. Trichomonas vaginalis vulvitis. May, 
809 
Granuloma, inguinale, gynecologic lesions. 
May, 773-786 

pyogenic, vs. condyloma latum. May, 
798 
Graves' scaphoid scapula. May, 716 
Griseofulvin, March, 278 
Gumma (s). May, 653-665, 667-697 

vs. pubic epithelioma. May, 802 



Haldrone, March, 418 
Harmonyl, March, 469 
Headache, classification, March, 455 
due to cranial arteritis, treatment, 

March, 454 
muscle-contraction, treatment, March, 

449 
of nasal vasomotor reaction, treatment, 
March, 453 



Cumulative Index 



819 



Headache (Continued) 

treatment, newer drugs in, March, 445- 

457 
vascular, of migraine type, treatment, 
March, 450, 452 

Heart, depolarization, electrical, in ar- 
rhythmias, March, 382 

Heart block, complete, treatment, March, 
319 

Heart disease, coronary, anticoagulant 
therapy, current myths and realities 
in, March, 355-370 
gastric and intestinal manifestations, 

Jan., 140 
hepatic manifestations, Jan., 137 

Hedulin, March, 358 

Hemoglobinuria, cold, paroxysmal. May, 
716 

Hemorrhage in duodenal ulcer, treatment, 
Jan., 94 

Heparin, as anticoagulant, March, 357 

Hepatic coma, management, Jan., 37-51 

Hepatitis, amebic, Jan., 166, 172 
gummatous, May, 681 

Hepatosplenomegaly, syphilitic, prenatal, 
May, 711 

Herpes progenitalis vs. chancre. May, 790, 
791 

Herpes zoster, penile, vs. chancre, May, 
792 

Hexetidine in urologic infections, March, 
294 

Hibitane in urologic infections, March, 295 

Higoumenakis' sign. May, 716 

Hirschsprung's disease, surgery in, indica- 
cations for, Jan., 227-230 

Hoffmann, Erich, May, 598 

Humatin, March, 276 

Hutchinson's teeth. May, 714, 715 

Hydrarthrosis, bilateral, in prenatal syph- 
"ilis. May, 712 

Hydrochloric acid, role, in healing of gas- 
tric ulcer, Jan., 103 

Hydroxyphenamate, March, 473 

Hydroxyzine, March, 475 

Hygroton, March, 330 

Hypercholesterolemia, treatment, March, 
347-354 

Hyperparathyroidism, shock in, March, 
326 

Hypertensin, March, 314 

Hypertension, alpha-methyldopa in, 
March, 330, 335-345 
newer drugs in, March, 329-333 

Hypoglycemia, shock in, March, 326 

Hypoproteinemia in gastrointestinal dis- 
eases, Jan., 76, 77 

Hypoxia, fetal, narcotic-induced, treat- 
ment, March, 433 



Ilosone, March, 270 

Imipramine, March, 495 

Infant, newborn, narcotic-induced respir- 
atory depression in, treatment, March, 
433 



Infections, urinary tract, newer antibac- 
terial drugs in, March, 293-304 

Intestines, diseases, protein-losing, Jan., 
75-91 
serum enzymes in, Jan., 209 
malabsorption in. See Malabsorption. 
obstruction, diagnosis, Jan., 68-72 
medical management, Jan., 67-74 

Intractability in duodenal ulcer, manage- 
ment, Jan., 100 

Intubation, intestinal, in intestinal ob- 
struction, Jan., 72 

Inversine, March, 314 

Iridocyclitis, syphilitic, May, 682 

Iritis, syphilitic, May, 629, 682 

Isocarboxazide, March, 490 

Isomerase, phosphohexose, serum, in liver 
disease, Jan., 201 

Isopropamide iodide, March, 402 

Isoproterenol, in arrhythmias, new light 
on, March, 381 
in shock, March, 314 

Isuprel, March, 314 

Itching. See Pruritus. 



Jaundice, drugs causing, Jan., 55, 57 

in heart disease, Jan., 139 

posthepatic, vs. intrahepatic cholestasis, 
methods of diagnosis, Jan., 53-65 
Joints, Glutton's, in prenatal syphilis. 

May, 712, 713 



Kanamycin, March, 267 

in urologic infections, March, 302 
Kantrex, March, 267 
Keflin, March, 280 
Keratitis, interstitial, in prenatal syphilis, 

May, 711 
Ketosis, diabetic, shock in, March, 326 



Laboratory procedures in diagnosis, of 
malabsorption, Jan., 117-136 
of syphiUs, May, 731-741 

Larynx, syphilis of, May, 679 

Lecithinase A, serum, in pancreatic dis- 
ease, Jan., 207 

Leukeran, March, 508 

Leukoplakia vs. mucous patches. May, 
806, 807 

Levallorphan, chemistry and pharma- 
cology, March, 422, 423 
clinical uses, March, 431 

Levanil, March, 477 

Levarterenol in shock, March, 314, 316 

Levophed, March, 314, 316 

Librium, March, 449, 472 

Lichen sclerosus et atrophicans vs. mucous 
patch. May, 808 

Lip, gumma of, May, 679, 680 

Lipase, serum, in pancreatic disease, Jan., 
207 

Liquamar, March, 357, 358 

Listica, March, 473 



820 



Cumulative Index 



Liver, abscess, amebic, Jan., 166, 172 
biopsy, in differentiation of primary 
hepatic and posthepatic cholestasis, 
Jan., 60 
carcinoma, metastatic, in colon cancer, 

palliation in, Jan., 222 
diseases, primary, cholestasis of, Jan., 53 

serum enzyme levels in, Jan., 196 
effects of heart disease on, Jan., 137 
syphilis of, May, 681 
Lung, amebiasis, Jan., 167 

carcinoma, metastatic, in colon cancer, 
palliation in, Jan., 224 
Lymphogranuloma venereum, gynecologic 

lesions of, May, 773-786 
Lyndiol, March, 532, 537, 540 



Malabsorption, diagnosis, laboratory 
procedures in, Jan., 117-136 
disorders of, classification, Jan., 118 
tests for, in protein-losing enteropathv, 
/an., 82 

Mandelic acid for urinary acidification, 
March, 296 

Marplan, March,^ 490 

Measles, immunization against, emerging 
picture of, March, 305-309 

Mecamylamine in shock, March, 314 

Medicine, private, role of, in eradication of 
syphilis. May, 571-581 

Megacolon, congenital, indications for 
surgery in, Jan., 227-230 

Megestrol, March, b^2, 533 

Mellaril, March, 465 

Melphalan in cancer, March, 509 

Meningitis, syphilitic. May, 701 
in newborn, May, 711 

Mepenzolate bromide, March, 405 

Mephenoxalone, March, 473 

Mephentermine in shock, March, 314 

Meprobromate, March, 473 

Meratran, March, 490 

Mercaptoethylguanidine for protection 
against radiation, March, 551 

6-Mercaptopurine in cancer, March, 508 

Mesulfin in urological infections, March, 
294 

Metaraminol in shock, March, 314, 316 

Methdilazine in pruritus, March, 415 

Methenamine for urinary acidification, 
March, 295 

Methicillin, March, 257 
in urologic infections, March, 302 

Methionine for urinary acidification, 
March, 298 

Methotrexate in cancer, March, 507 

Methoxamine in shock, March, 314 

3-0-Methyl-D-glucose in study of malab- 
sorption, Jan., 130 

Methyldopa in hypertension, March, 330, 
335-345 

Methyl-GAG, March, 516 

Methylphenidate, March, 489 

Methysergide maleate in vascular head- 
ache, March, 452 



Metronidazole in Trichomonas vaginalis 

urethritis, May, 77.0 
Miltown, March, 474 
Mitomycin C in cancer, March, 511 
Moderil, March, 468 

MoUuscum contagiosum, anal, vs. con- 
dylomata lata. May, 804 
Moniliasis, penile, vs. chancre. May, 793 
Monoamine oxidase inhibitors, March, 490 
Mouth, syphilis of. May, 628, 630, 678 
Mucous membrane, lesions, in syphilis, 

May, 627, 708, 709, 710 
Mucous patches. May, 630 

vs. leukoplakia. May, 806, 807 

vs. lichen sclerosus et atrophicans. 

May, 808 
vs. localized neurodermatitis. May, 
807 
Mutabase, March, 331 
Myleran, March, 508 

Myocardial infarction, anticoagulants in, 

March, 358, 363, 365 

long-term, March, 363, 365 

shock of, treatment, March, 315 

Myocarditis, gummatous. May, 685 

Myoepithelial anomaly of gallbladder, 

Jan., 10 
Myxedema, shock in, treatment, March, 
325 



Nafcillin, March, 260 

Nalidixic acid, March, 281 

in urologic infections, March, 299 

Nalorphine, chemistrv and pharmacology, 
March, 422, 423 ' 
clinical uses, March, 431 

Naloxone, chemistry and pharmacology, 
March, 422, 423 
clinical uses, March, 431 

Narcotic addiction, diagnosis, use of antag- 
onists for, March, 436 

Narcotic antagonists, pharmacology and 
clinical use, March, 421-443 

NegGram, March, 281 

in urologic infections, March, 299 

Neohydrin in urologic infections, March, 
298 

Neomycin, newer data on, March, 285 

Neo-Synephrine. See Phenylephrine. 

Neuritis, optic, antimicrobial agents caus- 
ing, March, 285 

Neurodermatitis, localized, vs. mucous 
patches, May, 807 

Neurosyphilis, May, 699-705 

in late congenital syphilis. May. 712 
spinal fluid tests for. May, 701, 703 
treatment. May, 703, 813 

Nialamide, March, 491 

Niamid, March, 491 

Nicotinic acid in hvpercholesterolemia, 
March, 350 

Nitrofurantoin, newer data on, March, 287 

Nitrogen mustard in cancer, March, 508 

Nonvenereal diseases of genitals and their 
differentiation from venereal diseases, 
May, 787-813 



Cumulative Index 



821 



Norethindrone for contraception, March, 

531 
Norethynodrel for contraception, March, 

531 
Nortriptyline, March, 497 
Nose, saddle, syphilitic, May, 714 

septal perforation, syphilitic. May, 714 
Nostyn, March, 477 
Novobiocin, March, 272 
Nylidrin in shock, March, 314, 315 



Oncovine, March, 512 

o-p'-DDD, March, 516 

Opipramol, March, 496 

Optic atrophy, syphilitic. May, 701 

Optic neuritis, antimicrobial agents caus- 
ing, March, 285 

Orbenin, March, 260 

Ortho-Novum for contraception, March, 
535, 537, 540 

Oslo study of natural course of untreated 
syphilis. May, 613-623 

Osteitis, gummatous. May, 673 
sclerosing, syphilitic. May, 673 

Ovulation, suppressants, clinical use, 
March, 529-545 

Oxacillin, March, 258 

Oxanamide, March, 474 

Oxyphencyclamine, March, 403 



Pain, continued, in chronic pancreatitis, 
Jan., 240 
in colon cancer, palliation, Jan., 224 
intractable, in duodenal ulcer, Jan., 100 

narcotic antagonists in, March, 435 
relief, use of antagonists alone for, 
March, 437 
Pancreas, diseases, serum enzymes in, 

Jan., 204 
Pancreatin, March, 395 
Pancreatitis, chronic, diagnosis and man- 
agement, Jan., 231-248 
relapsing, Jan., 232 
with continued pain, Jan., 238 
with diabetes mellitus, Jan., 237 
with steatorrhea, Jan., 238 
medical treatment, March, 389-397 
Pancrelipase, March, 395 
Para-aminopropiophenone for protection 

against radiation, March, 554 
Paramethasone in pruritus, March, 418 
Paresis, general. May, 701 
Pargyline, March, 492 
Parnate, March, 493 
Paromycin, March, 276 
Pediculosis pubis. May, 800 
Penicillin (s), happenstance (fallout) ther- 
apy, in cure of earlv syphilis, May, 
747-753 
in gonorrhea, May,_ 758, 762, 769 
in infectious syphilis. May, 634, 635, 811 
in neurosyphilis, May, 703, 813 
in prenatal syphilis, May, 718, 812 
reactions, March, 266 
semisynthetic, March, 255-263 



Penicillin G, potassium, March, 284 

Penicillin N, March, 284 

Penicillin V, newer data on, March, 284 

Pentolininium in shock, March, 314 

Peptic ulcer, complications, management 
of, Jan., 93-102 
serum enzymes in, Jan., 209 

Perforation, of duodenal ulcer, treatment, 
Jan., 99 
of esophagus, spontaneous, Jan., 3-8 

Periactin, March, 416 

Perichondritis, syphilitic. May, 676 

Periostitis, syphilitic, May, 673 

Pernicious anemia. See A nemia, pernicious. 

Pertofrane, March, 497 

Pharynx, syphilis of, late. May, 678 

Phenethicillin, March, 256 

Phenindione, March, 358 

Phenmetrazine, March, 489 

Phenothiazines as tranquilizers, March, 
460 

Phenoxybenzamine in shock, March, 314 

Phenprocoumon, March, 357, 358 

Phentolamine in shock, March, 314 

Phenylalanine mustard in cancer, March, 
509 

Phenylephrine in shock, March, 314 

Phenyramidol in headache, March, 449 

Pheochromocytoma, shock in, treatment, 
March, 324 

Phobex, March, 476, 494 

Phosphatase, alkaline, in liver disease, 
Jan., 196 

Phrygian cap, Jan., 14, 16 

Pinta, etiology, clinical course, epidemi- 
ology. May, 721, 723 

Pipethanate, March, 477 

Pipradol, March, 490 

Polarmine, March, 414 

Polyarteritis nodosa, gastrointestinal syn- 
dromes, Jan., 141 

Polyvinylpyrrolidone, P^Mabeled, for test- 
ing absorption, Jan., 131 
test, in protein-losing enteropathy, Jan., 
81 

Postgastrectomy syndrome, Jan., 182 

Potassium, quinidine and, antagonism of, 
March, 377 

Preludin, March, 489 

Prenatal syphilis. May, 707-719, 812 

Proctocolitis in lymphogranuloma in- 
guinale. May, 777, 779 

Proctoscopy in amebiasis, Jan., 163 

Promine in cancer, March, 513 

Propetazine, March, 465 

Propoxyphene hydrochloride in headache, 
March, 448 

Prostaphlin, March, 258, 302 

Prostate, carcinoma, hormone therapy, 
March, 516 

Protein absorption, measuring, Jan., 130 

Protein-losing enteropathy, Jan., 75-91 

Prothipendyl, March, 467 

Provest for contraception, March, 532, 533, 
540 

Pruritus, oral treatment, March, 411-419 
pathophysiology, March, 411 



822 



Cumulative Index 



Psoriasis vs. secondary syphilis, May, 796 
Public health, role of, in eradication of 

syphilis. May, 571-581 
Pyloric obstruction in duodenal ulcer, 

treatment, /an., 98 
Pyoderma, genital, vs. syphilis. May, 798 



QuiACTiN, March, 474 
Quinidine, potassium and, antagonism and 
synergism of, March, 377 



Radiation, ionizing, protection against, 
research in agents for, March, 547-561 

Rauwiloid, March, 468 

Rauwolfia alkaloids and fractions, March, 
466 

Reagin tests for syphilis. May, 731 

Rectum, lesions of, in lymphogranuloma 
inguinale, May, 774 

Regitine, March, 314 

Reiter's disease. May, 771 

Rescinnamine, March, 468 

Reserpine, March, 469 

Reserpine-thiazide combinations in hyper- 
tension, March, 329 

Resistopen, March, 258 

Respiratory depression, narcotic-induced, 
treatment, March, 432, 433 

Respiratory tract, syphilis of. May, 679 

Retine in cancer, March, 513 

Rhagades, syphilitic, May,^ 714 

Rhinitis in prenatal syphilis, May, 708 

Ricord, Phillippe, May, 597 

Ristocetin, March, 275 

Ritalin, March, 489 

RO 5-3307 in hypertension, March, 331 

Robinul, March, 402 

Roentgen diagnosis, of adenomyomatosis 
of gallbladder, Jan., 14-19 
of carcinoma of colon, Jan., 216 
of gastric ulcer, Jan., 105 . 
of intestinal obstruction, Jan., 70 

Roentgen treatment, preoperative, in car- 
cinoma of colon, Jan., 220 

Rokitansky-Aschoff sinuses of gallbladder, 
Jan., 10, 11 

Rupture of esophagus, spontaneous, Jan., 
3-8 



Saber shin. May, 716 

Saddle nose, syphilitic, May, 714 

Salamide, March, 448 

Salicylamide in headache, March, 448 

Sarcolysin in cancer, March, 509 

Scapula, scaphoid, May, 715 

Schaudilin, Fritz, May, 597 

Seromycin, March, 275 

Serotonin for protection against radiation, 

March, 554 
Shock, anaphylactic, March, 322 

bacteremic, March, 323 



Shock (Continued) 

in arrhythmias, March, 318 
in cardiac tamponade, March, 317 
in endocrine diseases, March, 324 
in myocardial infarction, March, 315 
in pulmonary embolism, March, 317 
in relation to surgery, March, 322 
oligemic, March, 321 
treatment, newer agents in, March, 
311-328 

Singoserp, March, 468 

Sinuses, Rokitansky-Aschoff, of gallblad- 
der, Jan., 10, 11 

Sinutab in headache, March, 454 

Skeletal system, syphilis of. May, 673-678 

Skin, lesions of, in infectious syphilis. May, 
627 
in late syphilis, May, 654 
in prenatal syphiUs, May, 708, 709, 
710 

Snuffles in prenatal syphilis. May, 708 

Sodium dextrothyroxine in hypercholes- 
terolemia, March, 348 

Sodium fusidate, March, 283 

Softran, March, 475 

Soma, March, 448 

Sonilyn, March, 303 

Spartase, March, 498 

Spinal fluid, tests, for syphilis. May, 701 

Spontin, March, 275 

Sprue, diagnosis, laboratory procedures in, 
Jan., 117-136 

Staphcillin, March, 257 

Staphylococcal infections, drug therapy, 
March, 263 

Steatorrhea, diagnosis, laboratory pro- 
cedures in, Jan., 117-136 
pancreatic, Jan., 238 

differentiation, Jan., 132 
tests for, Jan., 120, 123 

Sterisol in urologic infections, March, 295 

Steroid therapy in cancer, March, 513 

Stokes-Adams attacks, treatment, March, 
319 

Stomach, diseases, protein-losing, Jan., 
75-91 
freezing, in peptic ulcer, Jan., 101 
syphilis of. May, 681 
ulcer, diagnosis and treatment, indi- 
vidualization in, Jan., 103-115 

Stools, examination, for amebae, Jan., 164 
for malabsorption, Jan., 120 
fat in, clinical analysis, Jan., 120 

Streptomycin, in gonorrhea. May, 762 
newer data on, March, 284 

Striatran, March, 473 

Suavitil, March, 476, 494 

Sulfachlorpyridazine in urologic infections, 
March, 303 

Sulfhydryl inhibitors in cancer, March, 510 

Sulfonamides in urologic infections, March, 
303 

Sulfur mustards in cancer, March, 510 

Superinfections, induction by antibiotics, 
March, 288 

Sycotrol, March, 477 

Synalgos in headache, March, 454 



Cumulative Index 



823 



Syncillin, March, 256 
Syphilids, benign late, May, 654-664 
infectious stage, May, 627-630 
nonvenereal lesions resembling. May, 
790-809 
Syphilis, American Medical Association 
and, May, 583-586 
cardiovascular, May, 685-696 

treatment. May, 695, 813 
cluster interviewing, May, 650 
congenital. See Syphilis, prenatal. 
contact interviewing. May, 649 
control of, importance of contact in- 
vestigation in, May, 637-651 
course in Western World since 1500, 

May, 599 
diagnosis, new laboratory methods in. 
May, 731-741 
worldwide problems in, May, 721-730 
endemic, etiology, clinical course, epi- 
demiology. May, 721, 723 
epidemiology, importance in control. 
May, 639 
private patients lost to, May, 575 
eradication, role of public health and 

private medicine in, May, 571-581 
gummas of. May, 653-665; 667-697 
history of. May, 587-612, 671 
impact on family. May, 743-746 
incidence, past and present, May, 573, 

574, 599-610 
infectious. May, 625-636 

clinical manifestations. May, 627 
differential diagnosis. May, 632 
epidemiology, May, 632 
happenstance (fallout) cures, May, 

747-753 
laboratory tests. May, 631 
treatment. May, 632, 811 
intolerable nature of, need for recogni- 
tion, May, 577 
late, benign, May, 653-665, 667-697 
clinical manifestations, May, 654, 

667-697 
differential diagnosis, May, 657 
gumma formation in. May, 660 
incidence and distribution. May, 

670, 672 
laboratory tests. May, 657 
of eyes. May, 682 
of gastrointestinal tract. May, 681 
of mouth and pharynx, May, 678 
of respiratory tract. May, 679 
of skeletal system. May, 673-678 
serologic findings. May, 683 
treatment. May, 684, 813 
latent, clinical manifestations, May, 629 

treatment. May, 634, 811 
nonvenereal diseases and, differentia- 
tion. May, 787-813 
of nervous system, May, 699-705 
oral medication. May, 813 
origin of, May, 587 
prenatal, May, 707-719 

autoimmune phenomena. May, 716 
clinical manifestations. May, 708 
laboratory tests, May, 717 



Syphilis (Continued) 

prenatal, treatment. May, 718, 812 
primary, clinical manifestations. May, 
627 
treatment, May, 634, 811 
secondary, clinical manifestations. May, 
627 
treatment, May, 634, 811 
skeletal. May, 673-678 
skin and mucous membrane lesions. 

May, 627, 654 
stages of. May, 625 
symposium on, May, 571-813 
tests for. May, 631, 657, 731-741 
treatment, summary of, May, 811-814 
untreated, late manifestations. May, 669 
natural course of, Oslo study. May, 
613-623 
venereal, etiology, clinical course, 

epidemiology. May, 721, 723 
visceral, late manifestations. May, 667- 
697 
Syrosingopine, March, 468 



Tabes dorsalis. May, 701 

Tacaryl, March, 415 

Tamponade, cardiac, treatment, March, 

317 
Tao, March, 271 
Taractan, March, 464, 467 
Teeth, Hutchinson's, May, 714, 715 
Temari], March, 413 
Terephthalanilides, March, 516 
Tests, fluorescent treponemal antibody. 
May, 738 
for malabsorption in protein-losing 

enteropathy, Jan., 82 
for steatorrhea, Jan., 120 
in intestinal obstruction, Jan., 71 
laboratory, in diagnosis of malabsorp- 
tion, Jan., 117-136 
new, in diagnosis and management of 
syphilis. May, 731-741 
reagin, for syphilis, May, 731 
Reiter complement fixation. May, 7 

protein, May, 737 
serologic, for prenatal syphilis. May, 717 

for syphilis, May, 731-741 
spinal fluid, for syphilis. May, 701 
therapeutic, in gastric ulcer, Jan., Ill 
Treponema pallidum, agglutination. 
May, 735 
complement fixation. May, 736 

whole body. May, 736 
immobilization, May, 734 
immune adherence. May, 735 
methylene blue. May, 736 
treponemal, for syphilis. May, 733-740 
Wassermann reaction. May, 737 
Tetracycline (s), in gonorrhea. May, 762, 
769 
in syphilis. May, 635, 814 
newer data on, March, 286 
Thiolprives in cancer, March, 508 
Thioridiazine, March, 465 
Thio-TEPA in cancer, March, 508 



824 



Cumulative Index 



Throat, gumma of, May, 678 

Thrombosis, pathogenesis, March, 355 

Thrombotest, March, 357 

Thyroid analogues in hypercholestero- 
lemia, March, 348 

Thyroid gland, carcinoma, treatment, 
March, 515 

Timovan, March, 467 

Tindal. March, 465 

Tofranil, March, 495 

Tongue, gumma of. May, 679, 680 
secondary syphilis of. May, 630 

Trancopal, March, 472 

Tranquilizers, major, March, 459 
minor, March, 470 
new, March, 459-481 

Transaminase, glutamic oxalacetic, in 
liver disease, Jan., 198 
in pancreatic disease, Jan., 208 
glutamic pyruvic, in liver disease, Jan., 
200 

Transferase, ornithine carbamyl, serum, 
in liver disease, Jan., 203 

Tranylcypromine, March, 493 

Trasylol, March, 394, 396 

Treponemal tests for syphilis. May, 733- 
740 

Treponematoses, diagnosis, worldwide 
problems in. May, 721-730 
review of etiology, interrelationships, 
natural history and epidemiology. 
May, 721 

Triacetyloleandomycin, March, 271 
in gonorrhea. May, 762 

Triethylene melamine in cancer, March, 
508 

Trimeprazine in pruritus, March, 413 

Trimethaphan camphorsulfonate in 
shock, March, 314 

Triolein, P^i, in diagnosis of steatorrhea, 
Jan., 123 

Trypsin, serum, in pancreatic disease, 
Jan., 207 

Trypsin inhibitors, potential of, in pan- 
creatitis, March, 396 

Tubes, drainage, drugs to prevent encrus- 
tation, March, 294 



Urethritis, nonspecific. May, 767-772 
clinical course, May, 770 
treatment. May, 771 
Trichomonas vaginalis. May, 770 
Urinary tract, infections, newer antibac- 
terial drugs in, March, 293-304 



Vaccine, live virus, in measles, March, 306 
Vagina, lesions of, in granuloma inguinale, 
May, 781 
in lymphogranuloma inguinale. May, 
774 
Valpin, March, 404 
Vancomycin, March, 274 
Vascular disease, gastrointestinal mani- 
festations, Jan., 140 
Vasoxyl, March, 314 
Velban, March, 511 
Vinblastine in cancer, March, 511 
Vincristine in cancer, March, 512 
Viokase, March, 395 
Visceral syphilis, late manifestations. May, 

654, 667-697 
Vistaril, March, 475 

\ itamin A tolerance test for malabsorp- 
tion, Jan., 121 
Vitamin B12, deficiency, in pernicious 
anemia, Jan., 180 
radiocobalt labeled, absorption test, 
Jan., 131 
Vulva, lesions of, in granuloma inguinale. 
May, 781 
in lymphogranuloma inguinale. May, 
774 
Vulvitis, Trichomonas vaginitis vs. gon- 
orrhea. May, 809 



Warfarin sodium, March, 357, 358 
Wassermann, August von, May, 599 
Wassermann reaction, treponemal, May, 

737 
Wyamine, March, 314 



Ulcer, duodenal, complications, manage- 
ment of, Jan., 93-102 

gastric, diagnosis and treatment, indi- 
vidualization in, Jan., 103-115 
Ulcerative colitis. See Colitis, ulcerative. 
Unipen, March, 260 
Urease-blocking agents, March, 298 
Urethra, lesions of, in lymphogranuloma 

inguinale. May, 775, 778 
Urethral discharge, chronic, treatment, 

May, 771 



X-5079C, March, 279 
Xylose tolerance test in malabsorption, 
Jan., 82, 127 



Yaws, etiologv, clinical course, epidemi- 
ology. May, ^721, 723 



Zactirin, March, 448